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Annexe D - Études récentes


 

 

 


 

 

ANNEXE D

 

 

PUBLICATIONS SCIENTIFIQUES RÉCENTES

SUR

LA TOXICITÉ CHRONIQUE DES FLUORURES

 



 

FLUORIDE MOLECULAR MECHANISMS OF CYTOTOXICITY

Agalakova N. et G. Gusev, «Molecular Mechanisms of Cytotoxicity and Apoptosis Induced by Inorganic Fluoride.» Russian Academy of Sciences, International Scholarly Research Network, Journal of Cell Biology, Volume 2012,

Fluoride (F) is ubiquitous natural substance and widespread industrial pollutant. Although low fluoride concentrations are beneficial for normal tooth and bone development, acute or chronic exposure to high fluoride doses results in adverse health effects. The molecularmechanisms underlying fluoride toxicity are different by nature. Fluoride is able to stimulate G-proteins with subsequent activation of downstream signal transduction pathways such as PKA-, PKC-, PI3-kinase-, Ca2+-, andMAPK-dependent systems. G-protein-independent routes include tyrosine phosphorylation and protein phosphatase inhibition. Along with other toxic effects, fluoride was shown to induce oxidative stress leading to excessive generation of ROS, lipid peroxidation, decrease in the GSH/GSSH ratio, and alterations in activities of antioxidant enzymes, as well as to inhibit glycolysis thus causing the depletion of cellular ATP and disturbances in cellular metabolism. Fluoride triggers the disruption of mitochondria outer membrane and release of cytochrome c into cytosol, what activates caspases-9 and -3 (intrinsic) apoptotic pathway. Extrinsic (death receptor) Fas/FasL-caspase-8 and -3 pathway was also described to be implicated in fluoride-induced apoptosis. Fluoride decreases the ratio of antiapoptotic/proapoptotic Bcl-2 family proteins and upregulates the expression of p53 protein. Finally, fluoride changes the expression profile of apoptosis-related genes and causes endoplasmic reticulum stress leading to inhibition of protein synthesis.

Résumé de l’article préparé par Declan Waugh BSc. C.WEM. CEnv. MCIWEM. MIEMA. MCIWM.

«Malgré que beaucoup a été écrit au sujet des effets bénéfiques potentiels de faibles concentrations de fluorure sur la santé dentaire, toutefois les effets néfastes de l’exposition au fluorure sur la santé humaine n’ont reçu que très peu d’attention.  Ce document est une des premières revues importantes sur la toxicité du fluorure publiées dans une publication scientifique révisée par des pairs sur la biologie cellulaire.  Dans cette étude, des experts scientifiques en biologie cellulaire et en toxicologie biochimique de l’Académie des sciences de Russie ont concentré leur attention sur les mécanismes biochimiques moléculaires qui ont été démontrés comme étant responsable de la cytotoxicité et de l’induction de la mort cellulaire engendrées par le fluorure inorganique ainsi que les effets du fluorure sur les processus biologiques essentiels dans l’organisme.  Les auteurs affirment que malgré que la toxicité du fluorure est bien connue, elle a été ignorée pendant une longue période et ils soulignent que pendant que l’Organisation mondiale de la santé recommande une concentration optimale de fluorure dans l’eau potable, pour la prévention de la carie dentaire, lorsque le fluorure dans l’eau potable s’additionne aux autres sources alimentaires et aux breuvages ainsi qu’à celles des produits d’hygiène dentaire tels les dentifrices et les rince-bouche, l’apport optimal quotidien pour les individus se retrouve souvent dépassé.  Il en résulte une consommation de fluorure imprévisible et non contrôlée qui excède l’écart thérapeutique engendrant conséquemment des répercussions négatives sur la santé de cette population dans son ensemble.  Les auteurs notent que durant les dernières décades, on a établi que le fluorure était un puissant inducteur de l’apoptose (de la mort cellulaire) dans plusieurs types de culture cellulaire et dans les modèles expérimentaux sur des animaux.  Le fluorure lorsqu’il est ingéré dans l’organisme affecte pratiquement  tous les processus de signalisation intracellulaire connus  incluant les processus dépendant de la protéine G, les caspases et les mécanismes liés aux mitochondries- et- récepteurs de la mort, et aussi bien qu’en tant que déclencheur d’une gamme d’altérations métaboliques et  de transcription,  incluant l’expression de plusieurs gênes reliés à l’apoptose, menant ultimement à la mort cellulaire.  Il a été démontré que le fluorure  influence négativement  plusieurs fonctions métaboliques, structurelles et fonctionnelles de la cellule.  Les effets toxiques du fluorure incluent  une induction des réactions inflammatoires, des réponses contractiles de la cellule, une inhibition de la synthèse des protéines et de la progression du cycle cellulaire, du stress oxydatif et des dommages à l’ADN.  On a découvert que le fluorure peut  altérer les processus physiologiques et pathologiques cruciaux  pour les mécanismes de défense et de réparation de l’organisme.  Le fluorure s’est avéré en mesure de réduire le mécanisme antioxydant de défense affectant la capacité de l’organisme de neutraliser les radicaux libres et de combattre la maladie. 

Le fluorure affecte aussi la concentration cellulaire du calcium, interfère avec les réserves naturelles en calcium de l’organisme et agit en réduisant à la fois la fonction de la pompe à calcium (Ca2+) et de l’activation du canal calcique dans l’organisme, conséquemment, il perturbe les fonctions du cerveau, du cœur, des reins, du foie, de la glande pinéale et du pancréas. 

Puisque le fluorure perturbe les systèmes de défenses de l’organisme contre les oxydants, il stimule la peroxydation lipidique (LPO).  On croit maintenant qu’une peroxydation lipidique excessive pourrait être impliquée dans la carcinogénèse.  Il a aussi été démontré que le fluorure affecte directement les protéines de la famille Bcl-2 qui sont fondamentalement importantes dans la lutte contre le cancer.  Le fluorure est aussi reconnu comme un inhibiteur  de la voie glycolitique (glycolyse) et les auteurs notent que malgré que cet effet est connu depuis un certain temps il est souvent sous-estimé ou ignoré dans les études sur la cytotoxicité du fluorure et de l’apoptose (la mort cellulaire).  Le fluorure est reconnu comme étant en mesure de réduire la sécrétion de l’insuline et pourrait contribuer à l’obésité chez les individus ayant le diabète.  Les auteurs soulignent que les connaissances sur les processus intracellulaires impliqués dans le développement de la mort cellulaire induite par le fluorure est encore incomplète, notant que cela est probablement dû à la complexité et à la diversité des manifestations sous-jacentes de la toxicité du fluorure.  Ils concluent que des investigations intensives sont nécessaires afin d’identifier toutes les séries de manifestations impliquées dans le développement de la cytotoxicité et de la mort cellulaire engendrées par le fluorure ainsi que les mécanismes de leur régulation dans l’organisme humain.»


Olivier Barbiera, Laura Arreola-Mendozab, Luz Maria Del Razoa,

Molecular mechanisms of fluoride toxicity, Chemico-Biological Interactions 188 (2010) 319–333

a Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), México, D.F. 07360, Mexico

b Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo del Instituto Politécnico Nacional (CIIEMAD-IPN), México, D.F. 07360, Mexico

Keywords: Fluoride toxicity Oxidative stress Gene regulation Signal transduction

Fluorosis Drinking water

A b s t r a c t

Halfway through the twentieth century, fluoride piqued the interest of toxicologists due to its deleterious effects at high concentrations in human populations suffering from fluorosis and in in vivo experimental models. Until the 1990s, the toxicity of fluoride was largely ignored due to its “good reputation” for preventing caries via topical application and in dental toothpastes. However, in the last decade, interest in its undesirable effects has resurfaced due to the awareness that this element interacts with cellular systems even at low doses. In recent years, several investigations demonstrated that fluoride can induce oxidative stress and modulate intracellular redox homeostasis, lipid peroxidation and protein carbonyl content, as well as alter gene expression and cause apoptosis. Genes modulated by fluoride include those related to the stress response, metabolic enzymes, the cell cycle, cell–cell communications and signal transduction.

The primary purpose of this review is to examine recent findings from our group and others that focus on the molecular mechanisms of the action of inorganic fluoride in several cellular processes with respect to potential physiological and toxicological implications. This review presents an overview of the current research on the molecular aspects of fluoride exposure with emphasis on biological targets and their possible mechanisms of involvement in fluoride cytotoxicity. The goal of this review is to enhance

understanding of the mechanisms by which fluoride affects cells, with an emphasis on tissue-specific events in humans.

SUMMARY FINDINGS

The primary purpose of this review is to examine recent findings that focus on the molecular mechanisms of the action of inorganic fluoride in several cellular processes with respect to potential physiological and toxicological implications. The report highlights how drinking water is the primary source of fluoride exposure in humans. In this route of exposure, fluoride targets biological systems in the human body.

This review presents an overview of the current research on the molecular aspects of fluoride exposure with emphasis on biological targets and their possible mechanisms of involvement in fluoride cytotoxicity. The goal of this review is to enhance understanding of the mechanisms by which fluoride affects cells, with an emphasis on tissue-specific events in humans.

 This paper examines how fluoride affects cellular function, acts as an enzyme inhibitor in the body, is a mutagenic agent, induces chromosome aberrations and cytotoxic effects and causes chromosomal anomalies along with primary DNA damage in human cells.

The report examines how fluoride can stimulate cancerous tumor cells and promote their development, their invasive properties and their migration in the human body.

The report examines how fluoride exposure may contribute to impaired glucose tolerance and discusses the toxic effects of fluoride on insulin secretion and impairs glucose metabolism.


The report highlights how fluoride impairs the regulation of calcium levels in humans resulting in increased calcium retention in some tissues and reduces calcium transport and metabolism in the human body. Calcium regulation is critical for normal cell function, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signalling as well as for hormonal secretion in endocrine organs. The report highlights how all these mechanisms can also be targets of fluoride.

The report discusses how fluoride in drinking water coexists with several other xenobiotics, frequently metals such as lead, arsenic and aluminum and how fluoride can modify their kinetic and toxicity properties. It discusses how fluoride-aluminum complexes may result in a wide range of health effects, the interaction of arsenic and fluoride and how when they combine in drinking water increase the induction of genotoxic effects on humans. The report highlights the relationship between water fluoridation and elevated blood lead.

The report highlights that fluoride must be actively considered as a potent toxic compound in the field of toxicology, both in epidemiologic/ecological research and in fundamental or applied research and that much greater study is required to examin fully the impact of fluoride on biological systems. The report concludes that there is an absence of clear proof to counter the known and diverse toxic effects of fluoride on the human body, in particularly the toxicological effects of its combination with metalloids and metals and observes that extensive experiments are needed to conclusively determine the effects of such combinations on biological systems as well as to account fully for the different toxic effects of fluoride in general.


Rosangela M.M. Sawana, 1, Giselle A.S. Leitea, 1, Maria C.P. Saraivaa, Fernando Barbosa Jr.b, Jose E. Tanus-Santosc and Raquel F. Gerlacha «Fluoride increases lead concentrations in whole blood and in calcified tissues from lead-exposed rats» Toxicology. 2010 Apr 30;271(1-2):21-6. Epub 2010 Feb 25.

School of Dentistry of Ribeirao Preto, University of Sao Paulo (FORP/USP), Av do Café s/n, 14040-904, Ribeirão Preto, SP, Brazil

School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo (FCFRP/USP), Av do Café s/n, 14040-903, Ribeirão Preto, SP, Brazil

Faculty of Medicine of Ribeirao Preto, University of Sao Paulo (FMRP/USP), Avenida Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil

Abstract

Higher blood lead (BPb) levels have been reported in children living in communities that receive fluoride-treated water. Here, we examined whether fluoride co-administered with lead increases BPb and lead concentrations in calcified tissues in Wistar rats exposed to this metal from the beginning of gestation. We exposed female rats and their offspring to control water (Control  Group), 100 mg/L of fluoride (F Group), 30 mg/L of lead (Pb Group), or 100 mg/L of fluoride and 30 mg/L of lead (F + Pb Group) from 1 week prior to mating until offspring was 81 days old. Blood and calcified tissues (enamel, dentine, and bone) were harvested at day 81 for lead and fluoride analyses. Higher BPb concentrations were found in the F + Pb Group compared with the Pb Group (76.7 ± 11.0 μg/dL vs. 22.6 ± 8.5 μg/dL, respectively; p < 0.001). Two- to threefold higher lead concentrations were found in the calcified tissues in the F + Pb Group compared with the Pb Group (all p < 0.001). Fluoride concentrations were similar in the F and in the F + Pb Groups. These findings show that fluoride consistently increases BPb and calcified tissues Pb concentrations in animals exposed to low levels of lead and suggest that a biological effect not yet recognized may underlie the epidemiological association between increased BPb lead levels in children living in water-fluoridated communities.

Keywords: Fluoride; Lead; Whole blood lead; Bone; Dentine; Enamel; Fluoride-treated water; Fluosilicic acid; Lead toxicity; Environment


Sawan RM, Leite GA, Saraiva MC, Barbosa F Jr, Tanus-Santos JE, Gerlach RFFluoride increases lead concentrations in whole blood and in calcified tissues from lead-exposed rats. Toxicology. 2010 Apr 30;271(1-2):21-6. Epub 2010 Feb 25.

Source

School of Dentistry of Ribeirao Preto, University of Sao Paulo (FORP/USP), Av do Café s/n, 14040-904, Ribeirão Preto, SP, Brazil.

Abstract

Higher blood lead (BPb) levels have been reported in children living in communities that receive fluoride-treated water. Here, we examined whether fluoride co-administered with lead increases BPb and lead concentrations in calcified tissues in Wistar rats exposed to this metal from the beginning of gestation. We exposed female rats and their offspring to control water (Control Group), 100mg/L of fluoride (F Group), 30mg/L of lead (Pb Group), or 100mg/L of fluoride and 30mg/L of lead (F+Pb Group) from 1 week prior to mating until offspring was 81 days old. Blood and calcified tissues (enamel, dentine, and bone) were harvested at day 81 for lead and fluoride analyses. Higher BPb concentrations were found in the F+Pb Group compared with the Pb Group (76.7+/-11.0microg/dL vs. 22.6+/-8.5microg/dL, respectively; p<0.001). Two- to threefold higher lead concentrations were found in the calcified tissues in the F+Pb Group compared with the Pb Group (all p<0.001). Fluoride concentrations were similar in the F and in the F+Pb Groups. These findings show that fluoride consistently increases BPb and calcified tissues Pb concentrations in animals exposed to low levels of lead and suggest that a biological effect not yet recognized may underlie the epidemiological association between increased BPb lead levels in children living in water-fluoridated communities


Leite, G.A.S., Sawan, R.M.M., Teofilo, J.M. Porto, M., Sousa, F.B., Gerlach, R.F., «Exposure to lead exacerbates dental fluorosis, Arch Oral Biol, (2011),

Abstract Aim: Our aim was to test the hypothesis that co-exposure to lead and fluoride alter the severity of enamel fluorosis.

Materials and methods: Wistar rats were allocated in four groups :control, and 3 groups hat received water containing 100ppm of fluoride (F), 30ppm of lead (Pb),or 100ppm of F and 30ppm of Pb (F+Pb) from the beginning of gestation. Enamel analysis and F and Pb determinations in enamel, dentine, and bone were performed in 81-day-old animals. Fluorosis was quantified using a new fluorosis index based on the identification of incisor enamel defects(white bands and white islets, representing hypomineralization, and cavities) weighted according to their severity and quantity.  Hypomineralization was validated histopathologically by polarizing microscopy and microradiography. Scores were given by two blinded calibrated examiners (intra and inter examiner kappa values were 0.8 and 0.86, respectively).

Results: The control and the Pb groups presented normal enamel. The F+Pb group presented more severe enamel defects compared with the F group (P < 0.0001).

Conclusions: This study shows that lead exacerbates dental fluorosis in rodents, suggesting that co-exposure to lead may affect the degree of fluorosis


Jeff Prystupa. Fluorine—A current literature review. An NRC and ATSDR based review of safety standards for exposure to fluorine and fluorides. Toxicology Mechanisms and Methods, 2011; 21(2): 103–170

Independent Research Foundation, Toxicology Division, CO, USA

Abstract

Background: A review of the literature of the element fluorine and its bonded-form, fluoride, was undertaken. Generally regarded as safe, an expanding body of literature reveals that fluoride’s toxicity has been unappreciated, un-scrutinized, and hidden for over 70 years. The context for the literature search and review was an environmental climate-change study, which demonstrated widespread fluoride contamination by smokestack emissions from coal-fired electricity-generating plants. The objective of this review is to educate and inform regarding the ubiquitous presence and harmful nature of this now ever-present corrosive and reactive toxin.

Methods: Methods include examination of national health agency reviews, primarily the National Research Council (NRC), Agency for Toxic Substances & Disease Registry (ATSDR), standard medical toxicology references, text books, as well as reports and documents from both private and public research as well as consumer-based NGOs. Study criteria were chosen for relevancy to the subject of the toxicity of fluoride.

Results: Fluoride is the extreme electron scavenger, the most corrosive of all elements, as well as the most-reactive. Fluoride appears to attack living tissues, via several mechanisms. Fluoride renders strong evidence that it is a nonbiological chemical, demonstrating no observed beneficial function or role in organic chemistry, beyond use as a pesticide or insecticide. Fluorine has a strong role to play in industry, having been utilized extensively in metals, plastics, paints, aluminium, steel, and uranium production.

Conclusion: Due to its insatiable appetite for calcium, fluorine and fluorides likely represent a form of chemistry that is incompatible with biological tissues and organ system functions. Based on an analysis of the affects of fluoride demonstrated consistently in the literature, safe levels have not been determined nor standardized. Mounting evidence presents conflicting value to its presence in biological settings and applications. Evidence examined in this review of the literature, and specifically the recent report by the National Research Council (NRC), offer strong support for an immediate reconsideration concerning risk vs benefit. Consensus recommendations from several sources are presented.

Keywords: Fluorine; fluoride; water; teeth; bone; thyroid; depression; pollution; health; non-fever illness; disease vector; poison; chemical; corrosion; hypertension; hip fractures; immune; calcium;


Choi et al, Developmental Fluoride Neurotoxicity – A Systematic Review and Meta-Analysis, Environmental Health Perspectives 20-Jul-2012

July 20, 2012

ABSTRACT

Background: Although fluoride may cause neurotoxicity in animal models and acute fluoride poisoning causes neurotoxicity in adults, very little is known of its effects on children’s neurodevelopment.

Objective: We performed a systematic review and meta-analysis of published studies to investigate the effects of increased fluoride exposure and delayed neurobehavioral development.

Methods: We searched the MEDLINE, EMBASE, Water Resources Abstracts, and TOXNET databases through 2011 for eligible studies. We also searched the China National Knowledge Infrastructure (CNKI) database, as many studies on fluoride neurotoxicity have been published in Chinese journals only. In total, we identified 27 eligible epidemiological studies with high and reference exposures, endpoints of IQ scores or related cognitive function measures with means and variances for the two exposure groups. We estimated the standardized mean difference (SMD) between exposed and reference groups across all studies using random effects models. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking water fluoride as the only exposure. Cochran test for heterogeneity between studies, Begg’s funnel plot and Egger test to assess publication bias were performed. Metaregressions to explore sources of variation in mean differences among the studies were conducted.

Results: The standardized weighted mean difference in IQ score between exposed and reference populations was -0.45 (95% CI -0.56 to -0.35) using a random-effects model. Thus, children in high fluoride areas had significantly lower IQ scores than those who lived in low fluoride areas. Subgroup and sensitivity analyses also indicated inverse associations, although the substantial heterogeneity did not appear to decrease.

Conclusions: The results support the possibility of an adverse effect of high fluoride exposure on children’s neurodevelopment. Future research should include detailed individual-level information on prenatal exposure, neurobehavioral performance, and covariates for adjustment.


M. Diouf *, D. Cisse, C.M.M. Lo, M. Ly, D. Faye, O. Ndiaye

Femme enceinte vivant en zone de fluorose endémique au Sénégal et faible poids du nouveau-né à la naissance : étude cas–témoins Revue d’Épidémiologie et de Santé Publique 60 (2012) 103–108

Pregnant women living in areas of endemic fluorosis in Senegal and low birthweight newborns: Case–control study

Département d’odontologie, faculté de médecine de pharmacie et d’odontologie, université Cheikh Anta Diop de Dakar, BP 45391, Dakar, Fann, Sénégal

Reçu le 10 mars 2011 ; accepté le 9 septembre 2011

Résumé

Position du problème. – Dans les pays en développement, le taux de mortalité maternelle et néonatale est élevé. Parmi les causes de décès durant la période néonatale, le faible poids à la naissance reste déterminant. Une dose de fluorure supérieure à 2 mg/L provoque des altérations amélaires avec de possibles répercussions foetoplacentaire pendant la grossesse. L’objectif était d’étudier l’association entre la fluorose dentaire chez la mère et le faible poids du nouveau-né à la naissance.

Méthodologie. – L’étude, réalisée a` Diourbel (Sénégal), était de type cas–témoins. Elle portait sur 108 mères et leurs nouveau-nés de poids inférieur à 2500 g (cas) et sur 216 mères avec des nouveau-nés de poids supérieur ou égal a` 2500 g (témoins). Les variables sociodémographiques, les habitudes de vie, les antécédents et l’issue de la grossesse ont été recueillis. Les variables relatives à la fluorose concernaient l’eau consommée pendant la grossesse et la fluorose dentaire évaluée par l’indice de Dean. Les données ont été analysées par le logiciel R.

Résultats. – Les proportions de mères consommant de l’eau de forage étaient de 62 % chez les cas versus 43,5 % chez les te´moins. Le score 4 de l’indice de Dean concernait 25,9 % des cas contre 6,9 % des témoins. Le type d’eau consommée et le score modal de l’indice de Dean étaient significativement associés à la survenue du faible poids après ajustement sur la parité, la consanguinité, l’anémie et l’hypertension artérielle.

Conclusion. – Chez les femmes vivant en zone endémique, la fluorose dentaire est associée à la survenue d’un faible poids à la naissance.

# 2012 Publié par Elsevier Masson SAS.

Mots clés : Fluorose dentaire ; Faible poids à la naissance ; Zone endémique ; Sénégal ; Femme enceinte


Fluoride – the Danger that we must Avoid

H. BĂLAN

“Carol Davila”University of Medicine and Pharmacy, Bucharest

Medical Clinic Clinical Emergency Ilfov County Hospital, Bucharest, Romania

Abstract

One of the sad stories about what was considered to be a successful prevention of tooth decay is represented by fluoride supplementation of water and toothpastes. But even today, without knowingall the scientific reliable proofs, all the pieces of a very large puzzle, this action has many (especiallyin developing countries) promoters. That’s why we considered that a well-documented review in this domain would be of large interest, especially because the deleterious effects are many, accompaniedby a large number of threats for the health, and the benefits are lacking.

Key words: fluoride, toxic effects, oncologic impact, tooth decay.

Deux procès aux États-Unis qui ont prouvé la toxicité de la Fluoration:

Texas v. City of Houston, No. 80-52271 on the docket of the District Court of Texas in Harris County, 151st Judicial District.

Paul Aitkenhead et al. v. Borough of West View, filed of public record as No. GD-4585-78 on the docket of the Allegheny County Court of Common Pleas in Pittsburgh, Aitkenhead v. West View, 397 Atl. 2d 878 (Pa. Cmwlth. 1979