A safe drinking water standard for fluoride: LOAELS and protecting the most vulnerable'

1
A safe drinking water standard for
fluorideLOAELS and protecting the most
vulnerable.

• A presentation
• by
• Paul Connett, PhD
• Professor of Chemistry,
• St. Lawrence University,
• Canton, NY 13617
• Michael Connett
• Research Assistant
• Fluoride Action Network
• www.fluoridealert.org
• to
• National Research Council Subcommittee
• on fluoride in drinking water
• August 12, 2003
• National Academy of Sciences
• Washington, DC.

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References

• References listed in this presentation can be
  found at
• http//SLweb.org/bibliography.html
• Questions pconnett_at_stlawu.edu

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In this presentation we will

• Review the literature for the Lowest Observable
  Adverse Effect Levels (LOAELs) for various health
  outcomes.
• Discuss appropriate Margins of Safety (MOS) or
  Uncertainty Factors (UF).
• Propose a new MCLG for fluoride.
• Make some research recommendations.

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Reviewing the LOAELS for

• Skeletal Fluorosis (Clinical Pre-Clinical)
• Bone Fracture
• Dental fluorosis
• Pineal gland
• Thyroid gland
• Neurotoxicity
• Reproductive effects
• Hypersensitive reactions
• Osteosarcoma

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Skeletal Fluorosis
6
What is the estimated daily dose that causes
clinical skeletal fluorosis?
7

• "Crippling skeletal fluorosis might occur in
  people who have ingested 10-20 mg of fluoride per
  day for 10-20 years.
• (NRC 1993)

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How does this dose compare with the doses
expected in a 4 ppm community?
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5 of the water-consuming population drinks
more than 2.9 liters per day (Source US EPA,
data online) At 4 ppm, this would result in
daily consumption of 11.6 mg of fluoride per day
- from water alone.
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What are the F bone concentrations which cause
clinical skeletal fluorosis?
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DHHS Table (1991)
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How do these bone concentrations compare with
the bone concentrations expected in lt 4 ppm
communities?
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For humans exposure to 4 ppm fluoride in
drinking water yields an average 6400 ppm
fluoride in bone. (Gordon Corbin 1992)
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Fluoride Bone Concentrations at 4 ppm in Humans
Turner 1993
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What water concentrations of Fhave been
reported to cause skeletal fluorosis?
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In the United States a few cases of crippling
skeletal fluorosis have been reported in humans
only when the fluoride concentrations in drinking
water exceeded 8 mg/liter over many years. (NRC
1993)
17
Juncos Donadio 1972Journal of the American
Medical Association

• Two people with kidney impairment developed
  clinical skeletal fluorosis at
• 1.7 to 2.6 ppm fluoride in water. They were just
  17 and 18 years old.

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Recent follow-up to Juncos Donadio

• "Our study also demonstrated evidence of
  osteomalacia in rats receiving 15 ppm fluoride,
  or the equivalent of 3 ppm fluoridated water for
  humans. This finding is consistent with the case
  studies of Juncos and Donadio showing skeletal
  fluorosis in two individuals with renal
  insufficiency who were consuming water containing
  1.7-2.6 ppm fluoride. (Turner 1996)

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What are the F bone concentrations that cause
pre-clinical skeletal fluorosis?
20
DHHS Table (1991)
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How do these bone concentrations compare with
those found inlt 1.2 ppm communities?
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Bone levels in communities lt1.2 ppm F in water.
23
Eble et al ( 1992)
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Bone levels up to 6,500 ppm in unfluoridated
community (Sogaard 1994)
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Symptoms of Pre-Clinical Skeletal Fluorosis
Radiological findings of skeletal fluorosis may
not be evident (in the early stages) and
therefore most of these cases are either
misdiagnosed for other kinds of arthritis or the
patients are treated symptomatically for pains of
undetermined diagnosis (PUD). - Teotia 1976
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Bone Fracture
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Fluoride Bone Fracture3 Lines of Evidence1)
Animal Studies2) Human Clinical Trials3)
Epidemiology
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The significance of increased bone fractures
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Hip Fractures in the Elderly

• According to the CDC, 50 percent of the elderly
  who fracture their hip never regain an
  independent existence.
• www.cdc.gov/ncipc/factsheets/falls.htm
• According to the Osteoporosis Centre in
  Australia, 12 to 40 of the elderly who fracture
  a hip die within a year of the operation.
• www.osteoporosis-centre.org/oc_hip.htm

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The strength of the femoral neck is due mainly
to its shell of cortical bone. Computer analyses
indicate 90-95 of the strength of this region
is from cortical rather than trabecular bone.
(Gordon Corbin 1992)
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Fluoride Bone Fracture 1) ANIMAL STUDIES
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What are the F bone concentrations found to
reduce bone strength in animals?
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Fluoride Reduced Bone Strength in Animals
(Turner 1993)
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Several investigators - including ourselves -
have shown that bone strength decreases as bone
fluoride levels in the mineral phase increase to
beyond about 4,500 ppm. (Turner 1993)
36
How do these levels compare with the levels
expected in humans in lt 4 ppm communities?
37
For humans exposure to 4 ppm fluoride in
drinking water yields an average 6400 ppm
fluoride in bone. (Gordon Corbin 1992)
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HumanBone FLevelsin lt 1.2 ppmAreas
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Fluoride Bone Fracture 2) CLINICAL TRIALS
40
What are the average daily doses that have
produced fractures in clinical trials?
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Cumulative Doses in Clinical Trials
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What is the average cumulative dose used in
these trials?
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Cumulative versus daily dose

• The daily dose used in clinical trials is high
  (23-35 mg of F/day), but it is only used over
  short period (1-4 years).
• The range of daily doses for the general adult
  population is lower (1.6 6.6 mg/day, DHHS, 1991)
  but they occur over a much longer period, i.e.
  70 years
• Many people will experience cumulative doses over
  their lifetimes which exceed the cumulative doses
  which have caused increased hip fractures in
  clinical trials.

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What are the estimated F bone concentrations
after 2-4 years of clinical fluoride therapy?
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Estimated F Bone Concentrations after 2-4 years
of Therapy (lt3,000 ppm - 8,000 ppm)
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How do these concentrations compare with the
concentrations expected in 4 ppm communities?
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For humans exposure to 4 ppm fluoride in
drinking water yields an average 6400 ppm
fluoride in bone. (Gordon Corbin 1992)
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Fluoride Bone Fracture 3) EPIDEMIOLOGY
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Have epidemiological studies been conducted on
bone fracturerates in lt 4 ppm communities?
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Epidemiological studies

• Since 1990, there have been at least twenty
  studies (three remain unpublished) examining a
  possible connection between bone fractures and
  fluoride in drinking water. Of these twenty
  studies
• 1.) TEN have found an association between hip
  fracture and drinking water at lt 1.2 ppm.
• 2.) TWO have found a significant association at 4
  ppm (Sowers, 1991 Li et al, 2001)
• 3.) ONE found an association with all bone
  fractures at 1.5 5 ppm (Alarcon-Herrera et al,
  2001).
• 4.) SIX studies have found no association with
  hip fracture (although two of the six studies
  found an association with other types of
  fracture).
• 5.) ONE study found a reduction in hip fractures,
  accompanied by an increase in wrist fractures
  (Phipps et al, 2000).

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Li et al (2001)
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Dental Fluorosis
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Mild Dental Fluorosis Small opaque, paper white
areas scattered irregularly over the tooth,
involving less than 50 percent of the tooth
surface. (Dean 1942)
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Moderate Dental Fluorosis All enamel surfaces
of the teeth are affected, and the surfaces
subject to attrition show wear. Brown stair is
frequently a disfiguring feature. (Dean 1942)
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Severe Dental Fluorosis All enamel surfaces are
affected and hypoplasia is so marked that the
general form of the tooth may be affected. The
major diagnostic sign of this classification is
discrete or confluent pitting. Brown stains are
widespread and teeth often present a
corroded-like appearance. (Dean 1942)
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NRC (1993) photos
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What water concentrations of fluoride will
produce moderate severe dental fluorosis?
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At the current MCL of 4 ppm it is estimated that
over 30 of children will develop moderate or
severe dental fluorosis. (Dean 1942 NRC 1993)
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At concentrations of 1.8-2.2 ppm, it is estimated
that 8 of children will develop moderate
fluorosis, while 5 will develop severe
fluorosis. (Dean 1942 NRC 1993)
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At concentrations of 0.7-1.2 ppm, it is estimated
that 1.3 of children will develop moderate
dental fluorosis (Heller 1997)
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Is Dental Fluorosis aHealth or Cosmetic effect?
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To answer this question, we need to ask the
followinga) What are the psychological impacts
of moderate-to-severe dental fluorosis?b) Is
dental fluorosis a reflection of systemic health
damage?
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Psychological Impacta) social rejection,
embarrassment b) loss of sexual
attractiveness/appealc) potential detriment to
career
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Systemic health effectsa) Dental
fluorosis caused by inhibition of enzymes or
G-proteins (Den Besten 1999 Matsuo 1998) b)
What other enzymes/G-proteins in the body have
been effected?
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Dental Fluorosis an indicatorof bone
damage?
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Alarcon-Herrera et. al (2001)

• Alarcon-Herrera et. al looked at children in the
  Guardiana valley in Mexico, an area of high
  natural levels of fluoride.
• They examined the frequency of bone fractures in
  both children and adults as a function of the
  severity of dental fluorosis (a bio-marker for
  fluoride exposure in children)

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Fluoride and Childrens Bone

• Damage to childrens bones at 1 ppm was observed
  in one of the first fluoridation trials in the
  US, the Newburgh-Kingston, NY trial (Schlessinger
  et al, 1956). This study observed a higher
  incidence of cortical bone defects in the
  children in fluoridated Newburgh (13.5) than in
  non-fluoridated Kingston (6.5).
• (NAS, 1977)

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Increase in Dental Fluorosis Rates in 1 ppm
communities
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Dental Fluorosis

• PHSs recommended fluoride concentration in
  drinking water, 0.7 1.2 mg/L, was designed to
  maximize the prevention of dental caries while
  limiting the prevalence of dental fluorosis to
  about 10 of the population, virtually all of it
  mild to very mild.
• Health Effects of Ingested Fluoride,
• NRC, 1993, pp 4-5.

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Overall Dental Fluorosis Rates in Communities
with Optimal F

• 29.9 of US children have dental fluorosis on at
  least two teeth (Heller et al, 1997).
• In South Australia rates are 56 (Spencer et al,
  1996).
• Worldwide rates are estimated to be 48, with
  12.5 in categories of esthetic concern (McDonagh
  et al, 2000).

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Heller et al, 1997
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Heller et al (1997)

• children with DF
• F (ppm) on at least two teeth
• lt 0.3 13.5
• 0.3 - lt 0.7 21.7
• 0.7 - lt 1.2 29.9
• gt 1.2 41.4

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The Biochemistry of Fluoride
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Fluoride is Biologically Active

• It inhibits enzymes in vitro at 1 ppm, and in
  teeth and bones in vivo.
• It interferes with hydrogen bonding, the cement
  of biology (Emsley et al, 1981)
• It is mutagenic in-vitro (Caspary 1987), and
  maybe in-vivo (Joseph 1995 Sheth 1994, Wu 1995)
• It complexes with metal ions we need, eg Ca2,
  Mg2, Mn2 etc.
• It complexes with toxic metal ions and gets some
  of them to places they wouldnt otherwise go,
  e.g. Al3, Pb2 (Masters 1999, 2000 Varner 1998)
• In the presence of trace of Al3 it switches on
  G-proteins (Strunecka and Patocka, 1999, Li
  ,2003)).

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Fluoride the Pineal Gland
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Pineal Gland
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Pineal Gland
TRYPTOPHAN
Enzyme 1
Enzyme 2
SEROTONIN
Enzyme 3
Enzyme 4
MELATONIN
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Pineal Gland

• Luke (1994, abstract)
• Luke, Ph.D thesis (1997)
• Luke, Presentation at ISFR conference in
  Bellingham, WA (1998)
• Luke, Caries Research article (2001).

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Pineal Gland

• Fluoride accumulates in human pineal gland.
  Average of 9,000 ppm on calcium hydroxy apatite
  crystals (highest 21,000 ppm) (Luke, 2001).
• In animals (Mongolian gerbils) fluoride lowers
  melatonin production and shortens time to puberty
  (Luke, Ph.D. thesis, 1997).

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Earlier Onset of Puberty? (Schlesinger 1956)
86

• If it had been known in 1945 that F was so
  readily being taken up by the brain would they
  then have proceeded with their schemes without
  more investigations? (Luke 2003)

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Fluoride the Thyroid Gland
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Fluoride Thyroid

• German doctors have used sodium fluoride as a
  means to reduce thyroid activity in patients with
  hyperthyroidism.
• The doses used by Galletti and Joyet (1958) -
  2.3-4.5 mg of fluoride per day - are currently
  exceeded by people living in 1 ppm communities.

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Bachinskii 1985

• Altogether 123 persons were examined 47 healthy
  persons, 43 patients with thyroid hyperfunction
  and 33 with thyroid hypofunction. It was
  established that prolonged consumption of
  drinking water with a raised fluorine content
  (122 /- 5 mumol/l ( 2.3 ppm) with the normal
  value of 52 /- 5 mumol/l ( 1 ppm) by healthy
  persons caused tension of function of the
  pituitary-thyroid system that was expressed in
  TSH elevated production, a decrease in the T3
  concentration and more intense absorption of
  radioactive iodine by the thyroid as compared to
  healthy persons who consumed drinking water with
  the normal fluorine concentration. The results
  led to a conclusion that excess of fluorine in
  drinking water was a risk factor of more rapid
  development of thyroid pathology. (Bachinski,
  1985)

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Fluoride Reproductive System
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Fluoride Reproduction3 Human Studies
Conducted Since NRCs 1993 Review

• Freni SC. (1994).
• Susheela AK, Jethanandani P. (1996)
• Ortiz-Perez D, et al. (2003)

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Freni (1994) conclusion

• The study results and the wealth of animal data
  do raise the question whether public health
  concerns and toxicological research should not
  shift their focus from the isolated intake from
  fluoridated water to the potential toxicity of
  the total fluoride intake.

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Additional animal studies onF-reproduction since
NRC 1993 Review

• Chinoy 2001, 2000
• Collins 2001, 1995
• Elbetieha 2000
• Ghosh 2002
• Guna Sherlin 2001
• Hiyasat 2000
• Kumar 1994
• Narayana 1994
• Narayana Chinoy 1994
• Sprando 1997, 1996
• Verma 2001
• Zhao 1995

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Fluoride Neurotoxicity
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Fluoride Neurotoxicity

• Mullenix et al (1995).
• Chinese IQ studies with children (1995 ).
• Morgan et al (1998).
• Varner et al (1998).
• Masters and Coplan (1999, 2000).
• Calderon et al (2000).
• Xiang et al (2003).

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Fluoride Hypersensitivity
98
NRC Statement (1993)

• Reports of hypersensitivity reactions in humans
  resulting from exposure to NaF are mostly
  anecdotal (Arnold et al., 1960 Richmond, 1985
  Modly and Burnett, 1987 Razak and Latifah,
  1988) (NRC, 1993, p. 88, my emphasis).

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Reactions of the hypersensitive

• One percent of our cases reacted adversely to
  the fluoride. By the use of placebos, it was
  definitively established that the fluoride and
  not the binder was the causative agent. These
  reactions, occurring in gravid women and in
  children of all ages in the study group affected
  the dermatolgic, gastro-intestinal and
  neurological systems. Eczema, atopic dermatitis,
  urticaria, epigastric distress, emesis, and
  headache have all occurred with the use of the
  fluoride and disappeared upon the use of placebo
  tablets, only to recur when the fluoride tablet,
  was, unknowingly to the patient, given again
• Feltman and Kosel, 1961

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Fluoride Hypersensitivity

• Feltman R, Kosel G. (1961). Prenatal and
  postnatal ingestion of fluorides - Fourteen years
  of investigation - Final report. Journal of
  Dental Medicine 16 190-99.
• Shea JJ, et al. (1967).
• Lewis A, Wilson CW. (1985)
• Waldbott GL, Burgstahler AW, McKinney HL. (1978).
• Goldman D. (2001).

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Fluoride Osteosarcoma
102
Osteosarcoma

• "There was an observation in the
  Kingston-Newburgh (Ast et al, 1956) study that
  was considered spurious and has never been
  followed up. There was a 13.5 incidence of
  cortical defects in bone in the fluoridated
  community but only 7.5 in the non-fluoridated
  community... Caffey (1955) noted that the age,
  sex, and anatomical distribution of these bone
  defects are strikingly' similar to that of
  osteogenic sarcoma. While progression of cortical
  defects to malignancies has not been observed
  clinically, it would be important to have direct
  evidence that osteogenic sarcoma rates in males
  under 30 have not increased with fluoridation"
  NAS, 1977 (my emphasis)

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Osteosarcoma

• One animal study reported an equivocal increase
  in osteosarcomas in male rats, but not in female
  rats, at very high concentrations (100-175 mg/L).
  However, that result was not substantiated in a
  subsequent study in rats at even higher doses
  (NRC, 1993, p.1)

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Osteosarcoma

• In a 1998 interview the late Dr. John Colqhuoun
  asked, how many teeth saved would justify one
  child dying from osteosarcoma?

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Developing an MCLG for Fluoride
106
Developing an MCLG for fluoride

• Conventional approach
• Identify LOAELs (Lowest Observed Adverse
  Effect Levels)
• Apply an Adequate Margin of Safety to
  protect all members of society, including the
  most vulnerable

• Alternative approach
• Find a level known to be safe
• (Breast Milk 0.01 ppm)

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Applying an Adequate Margin of Safety

• If using the conventional approach towards
  developing an MCLG, there is some discretion as
  to how large the Safety Factors (aka Uncertainty
  Factors) should be.
• What is essential, is that - whatever its
  size - some Safety Factor be applied.
• Amazingly, in issuing their recent Upper
  Tolerable Intakes for Fluoride (10 mg/day), the
  IOM (1997), incorporated NO safety factor for
  crippling skeletal fluorosis (10-20 mg/day).
• It is critical that this Panel not make
  the same mistake as the IOM.

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Identifying LOAELS

• 0.3-0.7 ppm 21.6 dental fluorosis (Heller,
  1997)
• 0.7-1.2 ppm 29.9 dental fluorosis (Heller,
  1997)
• 0.9 ppm further reduction of IQ for iodide
  deficient chldren. (LinFa-Fu 1991)
• (1.0 ppm) bone fractures in children
  associated with the severity of dental fluorosis
  (Alarcon-Herrera, 2001)
• lt1.0 ppm accumulation in pineal gland (Luke,
  2001).
• 1.0 ppm earlier menstruation in girls
  (Schlesinger, 1956).
• 1.0 ppm increased cortical bone defects
  (Schlesinger, 1956)
• 1.0 ppm osteosarcoma in young males (SEER, 1991
  Cohn, 1992 - mixed)
• 10 ppm bone levels associated with arthritic
  symptoms.
• 10 ppm reduced cortical bone density (Phipps,
  2000)
• 10 ppm increased hip fracture (mixed epi.)

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Identifying LOAELS

• 1.0 ppm increased uptake of aluminum into rat
  brain and beta amyloid deposits (Varner, 1998)
• 2.3-4.5 mg (equiv. to 1.0 ppm) reduced
  hyperthyroidism (Galletti Joyet, 1958)
• 1.0 ppm 48 dental fluorosis (McDonagh, 2000)
• 1.0 ppm increased uptake of lead into childrens
  blood with silicofluorides in water fluoridation
  (Masters and Coplan, 1999, 2000)
• 1.2 ppm longer reaction times, poorer
  visuospatial recognition in children (Calderon,
  2000)
• 1.5 ppm mineralization defects in human bone.
  (Alhava 1985)

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Identifying LOAELS

• 1.6 ppm increased rate of sister chromatid
  exchange in humans (Sheth, 1994Joseph, 1995)
• 1.7 ppm clinical skeletal fluorosis in people in
  US with kidney impairments (Juncos and Donadio,
  1972)
• 1.8 ppm lowering of IQ (regression line est)
  (Xiang, 2003)
• 2.3 ppm impaired thyroid function (Bachinski,
  1985)
• 3.0 ppm reduced fertility (Freni, 1994)
• 3.0 ppm human-equivalent water levels that
  produce skeletal fluorosis in rats with kidney
  impairment. (Turner 1996)

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Identifying LOAELS

• 4.0 ppm produces daily doses (11.6 mg/day from
  water alone) that exceed the doses estimated to
  cause clinical skeletal fluorosis (10-20 mg/day
  for 10-20 years) (EPA data online NRC 1993).
• 4.0 ppm produces bone concentrations (avg. 6,400
  ppm) which exceed the bone concentrations
  (6,000) that cause clinical skeletal fluorosis.
  (Gordon Corbin 1992 Turner 1993)
• 4.0 ppm produces bone concentrations (avg. 6,400
  ppm) which exceed the bone concentrations (4,500
  ppm) found to weaken animal bone (Turner 1993).
• 4.0 ppm reduced bone density of cortical bone in
  humans (Phipps 1990 Sowers 1991).
• 4.0-4.3 ppm increased bone fractures in humans
  (Li 2001 Sowers 1991)

112
Determining Safety (Uncertainty) Factors

• For human studies, ideally we would want a margin
  of safety between the toxic dose and the
  regulatory dose of 100.
• We would like a factor of 10 to allow for
  different sensitivities in population.
• We would like another factor of 10 to allow for
  variation in daily dose in the population.
• However, depending upon the size of the study, at
  least one of these variables may have been
  accounted for. Thus for very large studies we
  would suggest a safety factor of 10.

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Determining Safety (Uncertainty) Factors

• For animal studies it is conventional to add
  another factor of 10 for extrapolation from
  animals to humans. This gives a safety factor of
  1000.

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MCLG calculations
115
Research recommendations

• 1) As requested by the Union at EPA, the tumor
  slides from the NTP study be re-examined by
  independent experts.
• 2) That bone levels of fluoride be ascertained at
  autopsy, during hip replacement and other bone
  operations wherever possible. These levels would
  be used to conduct more appropriate studies of
  the rates of arthritis, bone fractures, and
  osteosarcoma as a function of fluoride exposure
• 3) That the levels of fluoride also be determined
  in bone marrow as a function of age, to see
  whether fluoride makes it into the marrow at
  concentrations which could impair developing
  immune system cells (Sutton 1987 Sutton 1991).

116
Research recommendations

• 4) That levels of fluoride be determined in the
  pineal glands at autopsy, as well as from any
  archived material.
• 5) That Alarcon-Herreras 2001 study be repeated,
  i.e. that elsewhere an attempt be made to
  investigate bone fractures in children as a
  function of the severity of dental fluorosis.
• 6) That many more end points suspected to involve
  fluorides impact on children be investigated as
  a function of the severity of dental fluorosis
  (IQ , onset of puberty, hyperactivity etc).
• 7) That US medical schools be encouraged to
  investigate the pre-clinical symptoms of skeletal
  fluorosis, so that western doctors become more
  aware of the issue, and that the misdiagnosis of
  fluorosis with other diseases (e.g. arthritis) be
  reduced.

117
Research recommendations

• 8) That a thorough up to date and comprehensive
  study along the lines of the methodology of
  Feltman and Kosel (1961) be pursued to
  investigate the reactions of those suspected of
  being hypersensitive to fluoride.
• 9) That studies be directed towards possible
  synergistic interactions between fluoride and man
  made endocrine disrupters ( eg PCBs, DEHP,
  dioxins, furans and nonyl phenols) particularly
  on the reproductive system and the thyroid gland.
• 10) To further encourage the EPA to thoroughly
  investigate the long term toxicology of the
  siliconfluorides (both analytical grade and the
  industrial grade used in water fluoridation).

118
Research recommendations

• 11) Review all organofluorine pharmaceuticals to
  see if any are metabolized to free fluoride ion.