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もっと知りたいフッ素の話 その37 国際歯科連盟(FDI)がエナメル質形成不全(MIH)を総会の重要議題に!

反対運動の広がりの隙間をぬって、全国で学校等でのフッ素洗口が広がっています。今まで推進してこなかった、三重県、徳島県、石川県などが積極的な動きを始めています。むし歯予防に効果がないフッ化物応用について、世界が正しい議論をしてほしいと思います。フッ素に関する秋庭賢司さんからの最新情報です。

国際歯科連盟(FDI)がエナメル質形成不全(MIH)を総会の重要議題に

秋庭賢司

国際歯科連盟FDI(Fédération dentaire internationale)(注1)は2020年9月に上海で開催される総会でエナメル質形成不全(Molar Incisor Hypomineralization:MIH)を重要議題とする予定だ。その理由を世界中でMIHの発症率が13%に及ぶこと、原因が不明で発症前に診断できないこと等を挙げている。 

MIHとは

MIHは小児の永久歯(臼歯、切歯)にみられ急速に歯が摩耗し、エナメル質が消失するため、う蝕になりやすく治療の予後も悪い。対処療法としては、フッ化物の応用(信じられないことに歯を強くするためと称して推奨されている)、口腔ケアー製品の応用や修復治療を挙げている。

最近学校検診で、エナメル質の形成障害として白濁歯や斑状歯(歯フッ素症)ではなくエナメル質形成不全と診断される例をよく耳にする。

歯フッ素症はフッ素を原因とする歯の形成障害であり、臨床名(見た目)である斑状歯とほぼ同義語である。しかし従来から斑状歯の原因は多数列挙されており、全く同じ事が名前を変えて再登場している。

用語の解説によると(新谷誠康:エナメル質の障害,J Health Care Dent. 2010; 12: 18-24 Printed in Japan. All rights reserved)エナメル質形成不全(Molar Incisor Hypomineralization)はエナメル質減形成とエナメル質石灰化不全があり、遺伝性のエナメル質形成不全症(発症は約1万人に1人)とは区別される(表1)。 

エナメル質減形成は,エナメル質の基質であるタンパク質が形成されるときに障害があったもの,石灰化不全は,タンパク質はうまく合成されたが,うまく石灰化しなかったもの。実際は、どちらか判断がつかないことが多いのでただ単にエナメル質形成不全という。

どちらも形成時の障害であり、自然治癒はしないのでその痕跡を歯に留めている。

MIHの原因は?

MIHは問診によりほぼ原因が特定できる。永久歯の障害時期については表2を参照。

遺伝性疾患(表4)や症候性の疾患(表5)は原因が明らかであり、問題は表3に推測されている原因である。

原因不明とされるが、世界中で増加しているのは最後に挙げているフッ化物摂取であり、特に合衆国では青少年の歯フッ素症が疑問型を含めると72.2%、健康な歯の若者は28%しかいない。特に中重度は30.5%に及んでおり合衆国ではう蝕、歯周病と並び3大口腔疾患とされている(NHANES 2011-12 Journal of Dental Research 2019-Clinical&Trans actional Research C,Neurathほかhttps://doi.org/10.1177/2380084419830957)。

日本でもみられるMHI

日本でも千葉県の小学校4校で2121名を小児歯科専門医が検査した結果、11.92%にMIHを認め、そのうちの30名に実質欠損が認められた。問診の結果フッ化物含有ジェルやフッ素入り歯磨き剤を使用していた児童に発症割合が高い、としている(桜井ほか.J.Health care Dent.2014;14:6-12)。

また飲料水中フッ素の許容量に関する研究(1977年度医療助成金:1978年報告書昭和大学歯学部上田喜一教授)によると、沖縄本島コザ浄水場で1963年1月~1972年7月(日本に復帰)まで水道水のフッ素化(0.7~0.8ppm,1970以後は0.9ppm)が実施され、小中学生の軽度歯フッ素症(厚生省分類)がF化地区で7.88%に出現し、非F化地区では1.11%、 M1`(歯面50%以上が白濁) がF化地区では1.5%、非F化地区では0.09%であり17倍の出現は問題である、としている。

このように歯フッ素症と明言しないでエナメル質形成不全と称し、その原因を多数列挙して最も疑わしい原因であるフッ化物摂取を曖昧にするのは常套手段である。

 

表1  エナメル質の形成障害

Aエナメル質形成不全enamel hypomineralization: chronological disturbance

(1)エナメル質減形成 enamel hypoplasia

(2)エナメル質石灰化不全 enamel hypocalcification

Bエナメル質形成不全症amelogenesis imperfecta: hereditary nature

 

表2  永久歯の歯胚・歯冠・歯根の形成時期

歯 種 歯胚形成 石灰化開始 歯冠形成 歯根完成
第一大臼歯 胎生3.5~4月 出生時 2.5~3年 9~10年
中切歯 胎生5~5.25月 3~4月 4~5年 9~10年
側切歯 胎生5~5.5月 10~12月 4~5年 10~11年
犬 歯   胎生5.5~6月 4~5月 6~7年 12~15年
第一小臼歯 出生時 1.5~2年 5~6年 12~13年
第二小臼歯 7.5~8月 2~2.5年 6~7年 12~14年
第二大臼歯 8.5~9月 2.5~3年 7~8年 14~16年
第三大臼歯 3.5~4年 7~10年 12~16年 18~25年

 

表3  エナメル質形成不全 (MIH)について推測されている原因

  • 妊娠中の母親の病気,服薬,喫煙
  • ダイオキシン
  • 出産時の障害,早期産児
  • 授乳期あるいは生後1年以内の病気
  • 抗菌薬投与
  • ワクチン接種
  • フッ化物摂取

 

表4  Witcop’s Classification

Type I
低形成型
Type II
低成熟型
Type III
低石灰化型
Type IV
タウロドンティズム併発性
低成熟ー低形成型
常染色体性優性
常染色体性優性
常染色体性劣性
常染色体性優性
X連鎖優性
常染色体性優性
常染色体性劣性
常染色体性劣性
X連鎖 劣性
常染色体性優性
常染色体性優性
常染色体性劣性
常染色体性優性
常染色体性優性

 

表5  全身疾患と歯の関係.症候群に併発する場合

  • ダウン症候群
  • 結節硬化症
  • 表皮水疱症
  • ハーラー(フルラー)症候群
  • ハンター症候群
  • トリーチャー・コリンズ症候群
  • フェニルケトン尿症
  • 毛髪・歯・骨症候群
  • 副甲状腺機能低下症
  • 偽性副甲状腺機能低下症
  • レッシュ-ナイハン症候群
  • ビタミンD抵抗性くる病
  • ファンコーニ症候群
  • スタージ-ウェーバー症候群
  • ターナー症候群

 

NTP (National Toxicology Program)レポート2019年9月16日

フッ素暴露と神経の発育および認識への健康影響に関するNTPシステマティックレビューの草稿

DRAFT NTP MONOGRAPH ON THE SYSTEMATIC REVIEW OF FLUORIDE EXPOSURE AND NEURODEVELOPMENTAL AND COGNITIVE HEALTH EFFECTS

 合衆国HHS,NIH,NIEHS、NTP健康調査と翻訳部門(厚労省に相当)

Office of Health Assessment and Translation Division of the National Toxicology Program National Institute of Environmental Health Sciences National Institutes of Health  

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

P1~129の全ページの頭に書かれている。巻頭だけに書くのが普通、誰も責任を取らない。

This DRAFT Monograph is distributed solely for the purpose of pre-dissemination peer review and does not represent and should not be construed to represent any NTP determination or policy.

 

P7/135 Abstract

found support for an association between consumption of high levels of naturally occurring fluoride in drinking water and neurological effects in humans and recommended further investigation (NRC 2006).

The evidence for effects on learning and memory was strongest (moderate) in animals exposed as adults, and evidence was weaker (low) in animals exposed during development. (NTP (2016)).

Objective: To conduct a systematic review of the human, experimental animal, and mechanistic literature to evaluate the evidence.

Method:82 of the 149 human studies evaluated the association between fluoride exposure and neurodevelopmental or cognitive effects, and the remaining human studies evaluated thyroid effects or other potential mechanistic data. 35new experimental animal1 studies evaluating effects on learning and memory and/or motor activity and sensory effects of fluoride.

P8/135

Conclusion: The consistency is based primarily on higher levels of fluoride exposure (i.e., >1.5 ppm in drinking water). When focusing on findings from studies with exposures in ranges typically found in the United States (i.e., approximately 0.03 to 1.5 ppm in drinking water, NHANES (Jain 2017)) that can be evaluated for dose response, effects on cognitive neurodevelopment are inconsistent, and therefore unclear.

p9/135

This review was initiated in response to a nomination from the Fluoride Action Network.

The consistency of the results suggesting that fluoride may be neurotoxic warrants additional research (NRC 2006). Approximately 67% of the U.S. population receives fluoridated water through a community drinking water system (CDC 2013).

The U.S. Public Health Service (PHS) first recommended communities add fluoride to drinking water in 1962. PHS guidance is advisory, not regulatory, the decision to fluoridate water systems is made by state and local governments. PHS now recommends a fluoride concentration of 0.7 milligrams/liter (mg/L).

P10

Under the Safe Drinking Water Act, the U.S. Environmental Protection Agency (EPA) sets maximum exposure level standards for drinking water quality( maximum contaminant level goal: MCLG, a concentration at which no adverse health effects are expected), is 4.0 mg/L(naturally occurring not from water fluoridation) ,it is set to protect against increased risk of skeletal fluorosis. EPA also has a nonenforceable secondary drinking water standard of 2.0 mg/L, which is recommended to protect children against severe dental fluorosis.

The NRC(2006) review considered adverse effects of water fluoride[bone fractures and skeletal fluorosis, decreased intelligence quotient (IQ) and other neurological effects, cancer, and endocrine disruption (e.g., thyroid, parathyroid, pineal), metabolic function (e.g., glucose metabolism) ] focusing on a range of concentrations (2–4 mg/L) above the current 0.7-mg/L.

For many years, fluoride concentrations ranging from 0.8 to 1.2 mg/L (US DHHS 2015).

The NRC report concluded that the current MCLG should be lowered to protect against severe enamel fluorosis and to reduce the risk of bone fractures (NRC 2006).

The conclusions from the NRC review were the primary source of information for the potential hazard summary in a 2015 report by the U.S. Department of Health and Human Services (DHHS), Federal Panel on Community Water Fluoridation.

The NTP (2016) systematic review found a low-to-moderate level of evidence that learning and memory deficits occur in experimental animals ,exposed to fluoride by life stage of exposure (i.e., exposure during development or adulthood).

P11

Rate confidence、 four statements: High, Moderate, Low, or Very Low/No Evidence Available. Evidence ;five possible conclusions: Known, Presumed, Suspected, Not classifiable, or Not

NTP decided to conduct additional animal studies before carrying out a full systematic review to incorporate human, animal, and potentially relevant mechanistic evidence in order to reach hazard identification conclusions for fluoride and learning and memory effects in children and cognitive effects in adults.

PECO (Population, Exposure, Comparators and Outcomes) statements.

P14

Databases were searched and screened manually up to release dates of draft documents (August 20, 2019 for this document).

Databases Searched • BIOSIS (Thomson Reuters) • EMBASE • PsycINFO (APA PsycNet) • PubMed (NLM) • Scopus (Elsevier) • Web of Science (Thomson Reuters, Web of Science indexes the journal Fluoride) ,Fluoride Action Network website (http://fluoridealert.org/)

P16

Three Key Questions for observational human studies: confounding, exposure characterization, and outcome assessment. also for experimental animal studies: randomization, exposure characterization, and outcome assessment.

P18

The Four Risk-of-bias Rating : (Definitely, Probably) Low , (Probably ,Definitely) High

P19

Confidence ratings in the body of evidence as “high,” “moderate,” “low,” or “very low” is provided in the OHAT Handbook for Conducting a Literature-Based Health Assessment (http://ntp.niehs.nih.gov/go/38673, see STEP 5).

P20

Translate Confidence Ratings into Evidence of Health Effect Conclusions

High Level of Evidence : There is high confidence in the body of evidence for an association between exposure to fluoride and the health outcome(s).

Moderate Level of Evidence: There is moderate confidence in the body of evidence for an association between exposure to fluoride and the health outcome(s).

Low Level of Evidence: There is low confidence in the body of evidence for an association between exposure to fluoride and the health outcome(s), or no data are available.

Inadequate Evidence : There is insufficient evidence available to assess if exposure to fluoride is associated with the health outcome(s).

Evidence of No Health Effect : There is high confidence in the body of evidence that exposure to fluoride.

Integrate Evidence to Develop Hazard Identification Conclusions  Finally, the levels of evidence ratings for human and animal data were integrated with consideration of in vitro/mechanistic data to reach one of five possible hazard identification categories:

(1) Known, (2) Presumed, (3) Suspected, (4) Not classifiable, or (5) Not identified to be a neurodevelopmental hazard to humans (see Figure 3).

P22

Four factors to increased confidence: potency, dose-response, consistency in terms of cellular events observed at the same or lower doses than in vivo health effects, and consistency across cellular targets on the same functional pathway. Three factors decreased confidence: unexplained inconsistency across studies of the same endpoint, indirectness/applicability of the pathway for human health or concentrations for human exposure, and publication bias.

P23

149 human studies• 339 non-human mammal studies • 60 in vitro/mechanistic studies.

Number of Epidemiological Studies by Outcome and Age Categories

Including IQ Child60 (adult3) Learning/memory 4(3) Cognitive development 2

Cognitive impairment(5) ADHD child 5 etc.

P26

Summary: There is moderate confidence between high-fluoride exposure (mainly >1.5 ppm in water, but also high exposure via fluoridated salt and food) and decreased IQ or lower cognitive function in children. and low confidence in the body of evidence that fluoride exposure is associated with cognitive effects in adults. There is also a recent study of decreased IQ in children living in areas where drinking water fluoride concentrations are <1.5 ppm. Specifically, a study conducted in Canada observed a significant decrease in IQ in boys and girls associated with higher estimated total maternal consumption of fluoride during pregnancy from drinking water and other water-based beverages including black and green tea (Green et al. 2019).

There is a lack of evidence of an association between exposure to fluoride and cognitive effects in adults (Jacqmin et al. 1994, Li et al. 2016).

P34

ADHD: attention-deficit/hyperactivity disorder; GCI: General Cognitive Index; GM: geometric mean; HOME: Home Observation Measurement of the Environment; IQ: intelligence quotient; MSCA: McCarthy Scales of Children’s Abilities; WASI: Wechsler Abbreviated Scale of Intelligence (Spanish version); WISC-IV: Wechsler Intelligence Scale for Children-Revised; WRAML: Wide Range Assessment of Memory and Learning; WRAVMA: Wide Range Assessment of Visual Motor Ability

P35

confounding variables: age; child’s sex; race/ethnicity; maternal demographics (e.g., maternal age, body mass index [BMI]); parental behavioral and mental health disorders (e.g., ADHD, depression); socioeconomic status (e.g., maternal education, household income, marital status, crowding); smoking (e.g., maternal smoking status, secondhand tobacco smoke exposure); reproductive factors (e.g., parity); nutrition (e.g., BMI, growth, anemia); iodine deficiency/excess; minerals and other chemicals in water associated with neurotoxicity (e.g., arsenic, lead); maternal and paternal IQ; and quantity and quality of caregiving environment (e.g., Home Observation Measurement of the Environment [HOME] score).

P42 IQ in Children

Forty-one of the 48 studies reported an association between high fluoride exposure and decreased IQ in child.

Other Neurodevelopmental or Cognitive Effects in Children

Consistent results for associations of fluoride exposure with cognitive impairment in children other than decrements in IQ, such as hand-eye coordination, neurobehavioral assessment, behavioral capacity, and learning disabilities.

Because IQ cannot be assessed in infants, other neurodevelopmental tests were conducted.

P44   Cognitive Effects in Adults

Authors found no significant correlation between cognitive impairment and total daily water fluoride intake or urinary fluoride levels.

P46 Mechanistic Data in Humans

Due to the dynamic relationship between the thyroid gland, the pituitary gland, and the production and clearance of TSH, T3, and T4, the variations in results are not unexpected and do not eliminate the possibility of a mechanistic link between thyroid effects and neurodevelopmental or cognitive effects; however, the data do not support a clear indication that thyroid effects are a mechanism by which fluoride causes these effects in humans.

P47

Figure 7. Number of Lower Risk-of-bias Studies that Evaluated Thyroid Hormones in Children and Adults by Endpoint and Direction of Effect*

Figure 8. Number of Higher Risk-of-bias Studies that Evaluated Thyroid Hormones in Children by Endpoint and Direction of Effect*

P48

Animal Learning and Memory Data

P50

Figure 9. Number of Animal Mechanistic Studies for Fluoride by Mechanistic Category and Exposure Level*

There is some evidence of consistency in mechanistic effects, overall these data are insufficient to increase confidence or support a change to hazard conclusions.

Neurotransmitters

Twenty of 23 neurotransmitter studies assessed changes in brain cholinesterase activity associated with fluoride exposure at or below 20 ppm fluoride. Acetylcholine is a major neurotransmitter involved in learning, memory, and intelligence (Chen 2012, Gais and Schonauer 2017). AChE is responsible for the breakdown of acetylcholine in the synapses of nerve cells. Changes in cholinesterase, acetylcholine, or AChE could be related to effects on memory.

Decreases in cholinesterase will cause increases in acetylcholine, which can have a positive effect on learning and memory; however, long-term decreases in cholinesterase can lead to secondary neuronal damage occurring in the cholinergic region of the brain (Chen 2012).

P51

Biochemistry (brain/neurons)

P53

Oxidative stress 25studies

P54

Apoptosis/cell death   Inflammation 

thyroid effects are a requisite mechanism by which fluoride causes neurodevelopmental or cognitive effects in humans.

P55

Evidence Synthesis for Neurodevelopmental or Cognitive Effects

There is consistent evidence that exposure to fluoride is associated with cognitive neurodevelopmental effects in children. There is moderate confidence in the human data in children supported by a large number of functionally prospective cross-sectional studies.

Integration of these level-of-evidence conclusions supports an initial hazard conclusion of presumed to be a cognitive neurodevelopmental hazard to humans because of the extent, consistency, and magnitude of effect in the available data in children.

The human body of evidence in adults is considered inadequate to evaluate whether fluoride exposure is associated with cognitive effects due to low confidence(the data is not high enough to conclude that there is no effect).

The animal body of evidence is also considered to provide an inadequate level of evidence for cognitive effects in adults.

P56

Well-conducted Canadian and Mexican prospective cohort studies of children where repeated urinary fluoride levels were assessed during pregnancy [i.e., for full-scale IQ, a 4.49-point decrease in boys per 1-mg/L increase in maternal urinary fluoride, a 3.66-point decrease in boys and girls combined per 1-mg increase in maternal total fluoride intake, and a 5.29-point decrease in boys and girls combined per 1-mg/L increase in water fluoride concentration (Green et al. 2019); and a 2.5-point decrease in full-scale IQ in boys and girls combined per 0.5-mg/L increase in maternal urinary fluoride (Bashash et al. 2017)]

Effects in children

  • Human body of evidence: Moderate Confidence = Moderate Level of Evidence
  • Animal body of evidence: No studies available to specifically assess effects on learning and memory after exposure during developmental periods separately from other neurological effects including motor activity = Inadequate Level of Evidence
  • Initial hazard conclusion (Moderate Human x Inadequate Animal) = Presumed to be a Cognitive Neurodevelopmental Hazard to Humans
  • Final hazard conclusion (after consideration of biological plausibility) = Presumed to be a Cognitive Neurodevelopmental Hazard to Humans

 Effects in adults

  • Human body of evidence: Low Confidence with no discernible effect = Inadequate Level of Evidence
  • Animal body of evidence: No studies available to specifically assess effects on learning and memory after exposure in adulthood separately from other neurological effects including motor activity = Inadequate Level of Evidence
  • Initial hazard conclusion (Inadequate Human x Inadequate Animal) = Not classifiable
  • Final hazard conclusion (after consideration of biological plausibility) = Not classifiable

P58

DISCUSSION

Based on the systematic review of the evidence from 18 lower risk-of-bias studies, the NTP concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans.

P59

Generalizability to the U.S. Population

 For many years, fluoride concentrations were adjusted to levels between 0.8 and 1.2 mg/L in fluoridated community water systems in the United States. The U.S. Public Health Service recommended an adjustment downward to a fluoride concentration of 0.7 mg/L because of evidence of an increase in dental fluorosis in children (US DHHS 2015). In the 2013–2014 National Health and Nutrition Examination Survey (NHANES), a nationwide survey in the United States, data were released for fluoride concentrations in water for U.S. children and adolescents (≤19 years old).

P60

Table 8 provides a summary of children’s IQ studies that evaluated lower fluoride exposures (<1.5 mg/L) in drinking water and/or urine (assuming, for comparison purposes, an approximate 1-to-1 equivalence between drinking water fluoride and urinary fluoride concentrations:間違い;飲料水中のフッ素摂取量は飲み水のほか、清涼飲料水やジュースなどを含む。個人差もあるが、成人の水分摂取量は1日約2L、子どもは約1Lとしている。

フッ素の尿中排泄量は成人で約50%、発育中の子ども(6歳以下)は20%で残りの80%は体内(骨)に蓄積する。飲料水中フッ素濃度と尿中フッ素濃度を1:1としている。

飲料水1ppm(1mgF/1L)×2L(2mgF)×1/2=尿中1ppm

この比率は、成人でフッ素摂取量が水分だけの場合のみに可能、歯磨き剤などが追加された場合や子どもの場合は適用できない(飲料水1ppm×1L×1/4=尿中0.25ppm)4:1

米国ATSDR(Agency for Toxic Substances and Disease Registry)HHS:2003年の官報p157に記載

and provided information to evaluate dose-response in the lower fluoride exposure range (e.g., three or more fluoride exposure groups or dose-response curve provided). Based on review of these studies, there is uncertainty if IQ changes in children occur at lower fluoride levels.

P65

CONCLUSION:結論と内容が一致しない(二重基準):良心派の意見を忍ばせている。

NTP concludes that fluoride is presumed to be a cognitive neurodevelopmental hazard to humans. This conclusion is based on a consistent pattern of findings in human studies across several different populations showing that higher fluoride exposure is associated with decreased IQ or other cognitive impairments in children. However, the consistency is based primarily on higher levels of fluoride exposure (i.e., >1.5 ppm in drinking water). When focusing on studies with exposures in ranges typically found in the water distribution systems in the United States (i.e., approximately 0.03 to 1.5 ppm according to NHANES data) that can be evaluated for dose response, effects on cognitive neurodevelopment are inconsistent(矛盾), and therefore unclear(はっきりしない). There is inadequate(不十分) evidence to determine whether fluoride exposure lowers IQ or impairs cognitive function in adults.

P84

Evaluation is composed of federal staff and contractor staff support.

Contributors 36人  Reviewers  6人

 

(注1)国際歯科連盟(FDI)はスイスのジュネーヴに本部を持ち、歯科医師会や歯科関連団体で構成される連盟組織。1900年にフランスの歯科医師Dr. Charles Godonによりパリで設立された。130以上の国、地域から200以上の組織が参加している。
国際歯科連盟(FDI)はWHOと国際連合により公式に認められた団体であり、国際看護師協会、世界医師会、国際薬剤師・薬学連合とともにWorld Health Profession Allianceに参加している。

世界100万人の歯科医師を代表する組織として、WHOへの意見具申などを通し、国際的な健康増進政策などを支えている。
また、国際歯科連盟(FDI)の主目標の一つは全世界の歯科医師の情報交換の促進である。そのため、国際歯科連盟(FDI)では「International Dental Journal」、「Community Dental Health and Developing Dentistry」など多くの学術誌の刊行や、「World Dental Congress」を毎年世界各地で開催するなどの活動を行なっている。

 

日本歯科新聞記事(2020 1/1)参照

 

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