Cariology Final [Fluoride Metabolism and Toxicity: Levy]

Number of time Levy flipped to the next slide on accident

4

Elemental Fluoride (F2) is a yellowish green gas which readily

reacts to form salts:

- CaF2 (fluorite)

- Na3AlF6 (cryolite)

- Al2F2SiO4

Fluoride is ubiquitous: present in all

foods in trace amounts

Fluoride is ubiquitous: high levels in

teas and seafood

seawater is about

1 ppm F

Routes of intake

Air- as HF gas: quickly absorbed in lungs

Water

- inorganic- ~80% in 90min

- Organic or complexed (slower)

Inert physiologically - KPF6

Food

- Tea is high

- Milk is low

-- solids have slower absorption

Fluoride systemic distribution (IMAGE)

Absorption of Fluoride

Stomach and intestins

diffusion controlled

80% absorbed in 90 minutes

Need to treat overdose as fast acting poison

After ingestion with fluoridated water (GRAPH)

TA:

The first hour after ingestion it reaches its peak

Non-fasting fluoride absorption

- with cations only 80% absorption

- with bone meal, only 35-55% absorption

- With pablum (infant cereal) only 50% absorption

Mechanistically fluoride is complexed and therefore unavailable for absorption

Variable in Absorption

Fasting or non fasting

Liquid or solid

Rate dependent on acidity

Presence of food, milk, cations

Regulation of fluoride

Primary-skeletal tissues

Secondary-urinary excretion

F is physiologically different than other halogens

Deposited in bone

No accumulation by the thyroid

Rapid clearance by kidney

Deposition or retention of F

F is a bone-seeker - 95% found in skeleton

Steady-state occurs with constant intake

Dependent on maturation and previous exposure

Range of Plasma Fluoride

Typically follow water fluoride. as you increase water fluoride we see an increase in plasma fluoride

In adults, the water fluoride level and urinary excretion will equilibrate within ______ after introduction of fluoridated water

one week

Excretion of F

Rapid renal clearance of F

Urine 50% of intake at equilibrium

Urinary F is indicator of intake

Feces 5%

Perspiration 0-2%

Some features of F excretion by the kidneys (GRAPHS)

TA:

as you increase water F you get more F in the urine

at low pH we get little excretion of F at higher pH we get higher excretion of F

The total amount of fluoride in the body of an adult is about ______ with 95% of this in the ___

2.6, Skeleton

TA:

- This is a very little amount

An overdose of Fluoride can cause:

Acute poisoning- Extremely rare

Crippling skeletal fluorosis - Very rare in US

Mottled enamel (severe dental fluorosis)- relatively uncommon in US

Fatal dose of Fluoridated Water would be about ___ gallons consumed at one time

625

Signs of Fluoride overdoes

Nausea

Vomiting

Diarrhea

Cramping

Larger doses of Fluoride result in

Collapse

Coma

Death ~2-4 hrs

In high concentrations fluoride is a powerful metabolic inhibitor that blocks ______ and other divalent cation dependent enzymes

magnesium

In case of accidental overdose, symptoms can be treated with

milk of magnesia or other aluminum hydroxide preparations

Equivalent Amounts of F

Topical fluoride rule of thumb

Dental death due to Fluoride

Case report: 3-yr-old male for first dental visit

Clinical findings: caries free

Preventive procedures:

- mixed pumice with F (not water) as carrier for pumice

- Washed out pumice with 4% SnF2- not water

- Demonstrated rinsing with water

- Gave 1/2 lily cup of 4% SnF2 to child

Takeaway:

Multiple application of F that were not intended

Acute overdose

3 yrs:

- 14.4 Kg

- 500mg

6yrs:

- 21.1 Kg

- 750mg

9yrs:

- 29.5 kg

-1000 mg

Based on 35mg F/kg body wt as a lethal dose

F varnish applied is ~

2.3-5.0 mg

Peak plasma F in 2hrs: 3.2-6.3

comparable to brushing with F toothpastes

Contact allergy - rare but possible

Safe Water Drinking Act (1974)

Requires EPA "to determine the level of contaminants in drinking water at which no adverse health effects are likely to occur."

- Maximum contaminant level (MCL) at 4.0mg/L or 4.0ppm

- Water systems to remove contaminant

Balancing of the beneficial effects of protection from tooth decay and the undesirable effects of excessive exposures leading to discoloration"

- Secondary standard (SMCL) at 2.0 mg/L or 2.0 ppm

Takeaway

Maximum contaminant level is currently at 4.0mg/L or 4.0ppm

At 2.0 mg/L or 2.0 ppm have to let the consumer know every year

EPA and Drinking water main takeaway

they due reviews every so often and the never plan to do any changes

Recently (9/24/24)

- federal lawsuit against EPA ruled against EPA and said pretty much gotta look at fluoride a little more closely

Chronic effects of fluoride

Skeletal effects and bone fractures

Reproductive and development effects

Effects on the gastrointestinal system

Effects on the renal system

Carcinogenicity and genotoxic effects

Effects on IQ and related outcomes-current major emphasis

Effects of fluoride on teeth-fluorosis

Acute effects of fluoride: Gastrointestinal

Nausea, vomiting, diarrhea, excessive salivation, abdominal pain, and cramps

Acute effects of fluoride: Neurological

paresthesia, paresis, tetany, central nervous system depression, and coma

Acute effects of fluoride: Cardiovascular

weak pulse, hypotension, pallor, chock, cardiac irregularities and ultimate failure

Acute effects of fluoride: Blood chemistry

Acidosis, hypoglycemia, and hypomagnesemia

Toxic doses of fluoride: Probably toxic dose (PTD)

EXAM

5 mg F/kg body weight = 2.27 mg F/lb

The minimum dose that could cause toxic signs and symptoms including death and that should trigger immediate therapeutic intervention and hospitalization

Toxic doses of fluoride: Probable Lethal does (PLD)

EXAM

Death is likely. For example, in a child who ingests more than 15 mg F/kg body weight

Toxic doses of fluoride: Certainly lethal dose (CLD)

EXAM

32 to 64 mg F/kg body weight

Probably toxic dose

for a 2 year old child (average body weight 25 lbs or 10kgs

- 57 gms or 2 ounces of 1000 ppm fluoride toothpast

- 57 1.0 mg fluoride tablet

- 4.6 ml of a 1.23% APF gel

Fluoride toxicity: Acute

Levels of exposure vs the substance itself

many cases in the first half of the 20th century; rare today

Acute toxicity - is this a problem

Takeaway:

Thousands of calls to poison control

Dentifrices is the most common

Fluoride related reports to US poison control centers

Reported fatalities

TA:

death can occur rarely and can be multiple days later

Common signs and symptoms of acute fluoride toxicity: MILD TO MODERATE

Nausea

Bloody vomiting

Diarrhea

Drop in blood calcium,

local or general signs of muscle tetany

abdominal cramping and pain

Increasing hypocalcemia and hyperkalemia

Common signs and symptoms of acute fluoride toxicity: MODERATE to severe

The three C's

- coma

- convulsion

- cardiac arrhythmias

Recommended treatment: 5.0 mg/kg

Calcium orally (milk) to relieve GI symptoms. Observe for a few hours

induce vomiting is not necessary

Recommended treatment: 5-15 mg/kg

induce vomiting

calcium orally (milk)

Hospitalize and observe

Recommended treatment: 15 mg/kg

hospitalize immediately

induce vomiting

cardiac monitoring

calcium IV (Ca gluconate)

Supportive care

Calculations

Treatment of acute toxicity

Attempt to:

- minimize absorption from GI

- Increase urinary excretion

- maintain vital signs

Induce vomiting

- unless unconscious

calcium- can bind F due to strong affinity

- 1% calcium chloride or calcium gluconate

- or milk

Chronic: Skeletal effects and bone fracture

Skeletal fluorosis

Bone fractures:

Clinical trails with 50-80 mg NaF per day in those with osteoporosis

- 15 times higher than the intake from drinking water containing one ppm F

Epidemiological studies of bone fracture rates in fluoridated and non-fluoridated areas

conclusion:

Marginally protective in preventing vertebral fractures when the patient is adequately supplemented by calcium and Vit D along with NaF

Elevated risk of new non-vertebral fractures

Increased risk of bone fracture in populations exposed to water fluoride at 4 mg/L or greater

Reproduction and development effects

animal studies

- fluoride concentrations of 100-500 mg/L

Takeaway:

- no evidence in the literature suggesting a link

Developmental effects

fluoride concentration in fetal cord is 60% of the maternal serum concentration

- fluoride crosses the placenta

conditions studied are:

- spina bifida

- sudden infant death

- down's syndrome

takeaway:

NRC 2006 - overall developmental effects of fluoride are minimal

Child development:

Sub-study of the newburgh kingston study

complete physical examination physical measurements and laboratory and radiographic studies

takeaway:

NO difference in general health bone density hearing bunch of shit that wasn't any different

Effects on the gastrointestinal system

Animal studies:

- fluoride concentrations of 190 mg/L and higher

industrial workers with exposure to high concentration of fluoride dust

These doses are far higher than those to which typical human populations are exposed and therefore been considered of not much consequence

Effects on the renal system

Animal studies

- fluoride concentrations of 100-380 mg/L

Epidemiological studies

animal studies: Necrosis of proximal renal tubules interstitial nephritis and dilation of renal tubules

PHS: no human kidney diseases from long term non occupational exposure to fluoride concentrations in drinking water up to 8 mg/L

NRC: No human studies on drinking water containing fluoride at 4 mg/L in which gastrointestinal and renal effects were carefully documented

Carcinogenicity and genotoxic effects

Animal studies

- fluoride concentrations of 25 100 and 175 mg/L

Epidemiological studies

- NCI

PHS: the relative mortality rates from cancer including cancer of the bones and joints were similar after 20-35 years of fluoridation as they were in the years preceding fluoridation

NRC

- the evidence on the potential of fluoride to initiate or promote cancers is tentative and mixed

Several more recent high quality studies have found no association between F and osteosarcoma

Early studies of F and IQ

1) Several dozen early, low quality studies mostly from china and other places with environments very different from U.S including high F, mercury, lead, etc

2) More recent cohort studies from Mexico and Canada got more publicity since closer to US and in better journals, despite having major methodological limitations

Takeaways:

if IQ was really compromised with F (like with lead and mercury) it would be a very major concern

Early studies had a lot of other contaminants

More recent studies in places closer to the US have gotten publicity but still have major methodological limitations. Meaning their conclusions need to be taken with caution.

National Toxicology Program (NTP) Review of fluoride

NTP from 2015-2024 reviewed animal and human evidence about F and neurodevelopment

- Part of the federal government-

Early draft shared with National academics of science, engineering and medicine (NASEM)

Final report

changed from original to a state of the science concerning fluoride

Takeaway:

The initial draft called fluoride a neurotoxicant (messing up the brain development)

Final report

- changed from original

- Removed the wording of neurotoxicant

- Did not properly consider the study biases nor separately consider high vs low F levels

Lot of deficiencies

Federal Court case against CWF

- Plaintiffs sues EPA : Wanted the court to rule there could not be water fluoridation allowed by the EPA due to reductions in IQ and other health concerns

- Judge kept delaying it. Waiting for the NTP report

- Judge decided that the EPA needed to respond the possible safety concerns even though the science was far from settled

EPA appealed the court decision on 1/17/25

takeaway:

Even though there was not proof of risk judge decided there's enough questions and concerns about water fluoridation.

EPA is reviewing the science now

JAMA Peds Meta-analysis and editorials (published online on 1/6/25)

Fluoride exposure and children's IQ scores: a systamatic review and meta-analysis - original investigation: Kyla W. Taylor et al

Takeaway:

reported inverse associations and a dose response association between fluoride measurements in urine and drinking water and children IQ

Limited data and uncertainty in the dose-response association between fluoride exposure and children's IQ when Fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L

Had some bias

70% of the studies were rated high risk of bias

Had tons of data and looks impressive but since it was all observational studies it is suggested that it should be used to generate hypotheses only about future research not for strong statements that affect policy

JAMA Peds Meta-analysis and editorials (published online on 1/6/25)

Caution needed in interpreting the evidence base on Fluoride and IQ : Steven M Levy

wrote an editorial reviewing an article. was told the manuscript was conditionally accepted and that they already had an editorial to endorse it and wanted Levy to let them know his thoughts.

Told them he couldn't endorse it because it had some major problems

Takeaway:

Contacted them and said that he would not write a favorable report and that the authors needed to look at some of their major problems

Later was told they disregarded another colleagues comments as well.

within 24 hours it was still accepted

They were more interested in publicity rather than the best science

main conclusion:

- There was very few valid data from which to include that community water fluoridation benefits should be taken away

JAMA Peds Meta-analysis and editorials (published online on 1/6/25)

Time to reassess systemic fluoride exposure, again- editorial: Bruce P. Lanphear et al

These authors did a good job. Told a good story emphasized several things that were true but also misleading:

Said we didn't need water fluoridation because fluoride is mostly topical (well water fluoridation is topical as well)

They are essentially saying in this that we should stop water fluoridation until we know it is entirely safe (want to stop and reevaluate) the problem is that if we stop we might not ever get it going again and the current science is saying we are chilling and don't need to stop so why risk that.

Two recent articles of importance:

- A well done cohort study - from Spain:

Found better IQ in boys with more F

Another excellent cohort study- from Australia

- Slightly higher IQ levels for both those with lifelong CWF and partial CWF than those with none

Takeaway

The study provided consistent evidence that early childhood exposure to fluoride does not have effects on cognitive neurodevelopment

Kumar et all Meta-analysis (2023)

They properly separated F levels relevant to CWF from much higher ones to analyze separately

Found no association of lower IQ with F in areas with levels close to CWF levels

Possible elevated risk only in high F situations

Takeaway

Did a good job separating cofounding factors from flouride and showed that F at the proper concentration didn't cause lower IQ

Kumar Continued: GRAPH

Consistant evidence when we are talking about non-fluoridated and fluoridated that there is no concerned

Some efforts/ results in progress

Levy, Kumar, Warren (UNPUBLSIHED, 2025)

Only the high fluoridation has the reduction. Leading to high urinary fluoride.

Kumar, Levy, and Warren unpublished

Subgroup analysis shows that there is no association between urinary fluoride and IQ in non-endemic areas

Summary of everything:

No clear negative health effects from doses used in community water fluoridation

Only effects:

- Caries reduction

- Mild dental fluorosis risk