UNITED STATES ENVIRONMENTAL PROTECTION
AGENCY
WASHINGTON. D.C. 20460
OFFICE OF WATER
MEMORANDUM
DATE: May 1, 1990
SUBJECT: Fluoride Conference to Review the NTP
Draft Fluoride Report
FROM: Wm L. Marcus, Ph.D., Senior Science Advisor,
Criteria & Standards Division, ODW (WH-550D)
TO: Alan B. Hais, Acting Director, Criteria &
Standards Division, ODW (WH-550D)
The conference was held in RTP at the NIEHS headquarters on April
26, 1990. The subject of the conference was a peer review of the
NTP draft report on the toxicology and carcinogenesis studies of
Sodium Fluoride in F344/N Rats and B6C3F Mice (Drinking Water Studies)
NTP Report Number 393. Dr. Robert Scala was to chair this meeting
but was unable to attend because of ill health. Dr. Michael Gallo
was appointed acting Chairperson. One of the attenders seated with
the panel members was David Rall, Ph.D., M.D., Director of NIEHS.
Dr. Rall took an extremely active interest in the proceedings and
remained seated for the entire proceedings with only two minor interruptions.
The most disturbing part of the report was the continual reference
to the historical controls as having the same or higher cancers
as the test groups. On pages 89 - 90 of the report starting with
the last paragraph the authors state the following:
An important consideration which limits the usefulness of the historical
control data base in the current studies is that the diet used in
all other NTP studies had not been closely monitored for fluoride
content. Fluoride concentrations in typical batches of NHI-07 diet
range between 28 and 47 ppm (.7 and 1.2 mg/kg/day)(Rao and Knapka
(1), 1987). Assuming a minimum bioavailability of 60% (Tests show
66% absorption page I-18), the historical database animals actually
constitute a group receiving sufficient fluoride to place them between
the low- and mid-concentration group in the current (the studies
reviewed at RTP at the conference). The fact that this fluoride
is available for absorption from the standard diet is supported
by the levels of fluoride found in the bones of animals maintained
on this diet in the six months studies (Appendix I). (The levels
in the bones of the rats on the standard NHI chow was ten [10] times
the levels of those fed the semisynthetic diet and deionized water,
0.922 vs 0.0901). If the fluoride [is] in fact influencing the "spontaneous
" or background incidence of osteosarcoma in male rats, comparisons
with those in the historical database maybe misleading. This forces
an even greater reliance on the within-study comparisons, ie., the
incidences of the dosed groups compared with the concurrent control,
in the interpretation of the results of the sodium fluoride studies.
When I plotted a bar graph of osteosarcoma in male rats and placed
the historical controls on the graph 0.6% is just where expected.
This helps demonstrate a relationship between osteosarcoma and fluoride.
The purpose of such graphs is to predict occurrence. Since the historical
controls comprise some 6,000 animals, this data point is extremely
significant compared to the other three. Osteosarcoma is an extremely
rare animal tumor and may be the result of the variable high fluoride
content in the feed. In order to demonstrate this, all that need
be done is require that the fluoride content of animal chow be lowered
dramatically and that fluoride be removed from the water given to
the animals under study.
The dose of fluoride to which the concurrent controls were exposed
is 0.2 mg/kg/day. A 70 kg man who drinks 2 liters daily is exposed
to 0.03 mg/kg/day. The "control" animals were exposed
to an amount of fluoride six to seven (6-7 X) greater. Lois Gold,
Ph.D. of the review panel concluded that, "this group of animals
therefore, can hardly be termed a control group. It can best be
described as a lowest dosed group." This is an important consideration
because as the document reports on page 9, the levels of fluoride
in bone are linearly dependent upon dose and length of exposure
("depends upon total intake") in people. The level of
fluoride in ashed samples of bone of 20-30 year old people is 200
- 800 mg/kg compared to 70 to 80 year old people of 1,000 - 2.500
mg/kg. In the document, the authors cited Zipkin (2) who reported
on bone fluoride concentrations in four groups of individuals with
average ages of 56 to 76 who lived in areas with fluoride concentrations
in drinking water of 0. 1, 1, 2.6, or 4 ppm The relationship to
bone fluoride concentrations and water fluoride content was linear;
bone fluoride ranged from about 800 to 7,000 ppm ash with increasing
water fluoride."
In the animal studies the levels of fluoride (Appendix I) found
in the bones of the animals were the same as or lower than those
found in people. The highest dosed level of rats had lower levels
of fluoride in their bones (5,470 ppm) compared to people (7,000
ppm) at the MCL of 4 ppm. This can be interpreted as people who
ingest drinking water at the MCL have 1.3 times more fluoride in
their bones than male rats who get osteosarcoma This is the first
time in my memory that animals have lower concentrations of the
carcinogen at the sight of adverse effect than do humans. An important
toxicologic consideration is that a toxic substance stores at the
same place it exerts its toxic activity. This is true of benzene
and now for fluoride. Fluoride however, is at twice the concentration
in human bones compared to benzene which is 10 to 100 [times] greater
in animal marrow. This portends a very serious problem. One would
expect to be able to discern a carcinogenic effect in the exposed
population when compared to the unexposed population especially
if data exist on the populations before fluoridation.
Yiamouyiannis and Burk published epidemiology studies that have
since been revised twice (3), by Burk (former head of the Cytochemistry
section at NIH). In these extensively peer reviewed papers, the
authors found that about 10,000 deaths a year are attributable to
fluoride water treatment. The U.S. Public Health Service (U.S.PHS)
criticized the original studies by erroneously asserting that the
results reported by the authors were a result of changes in the
age, race and sex composition of the sample. The U.S.PHS made mathematical
errors and did not include 90% of the data. U.S.PHS method of analysis
when applied to the database, confirmed that 10,000 excess cancer
deaths yearly were linked to fluoridation of water supplies. This
evidence has been tested most recently in the Pennsylvania Courts
and found scientifically sound after careful scrutiny.
There were three different short term in vitro tests performed on
fluoride and all these tests proved fluoride to be mutagenic. An
Ames test was performed and reported to be negative. Bruce Ames,
in a letter to Arthur Upton introduced in the Congressional Record,
stated that his test system was inappropriate for fluoride testing
based on a number of technical considerations. EPA's own guidelines
require that in vitro tests be taken into consideration when found
positive. In this case, the mutagenicity of fluoride supports the
conclusion that fluoride is a probable human carcinogen.
Melvin Reuber, M.D, a board certified pathologist and former consultant
to EPA and part time EPA employee, reviewed some of the pathology
slides and the Battelle report. Dr. Reuber has had his pathologic
diagnoses questioned several times in the past. When an independent
board together with Dr. Reuber went over the slides his opinion
was always upheld. He first published the work that identified hepatocholangiocarcinoma
as a pathologic entity. The report changed Battelle's board certified
veterinary pathologists diagnoses from hepatocholangiocarcinoma
to hepatoblastoma and finally to hepatocarcinoma. Dr. Reuber reviewed
the pathology slides and stated that these lesions are indeed hepatocholangiocarcinoma.
Because Dr. Reuber first identified and published his findings on
this tumor, I trust his opinion in this matter. These tumors are
extremely rare. Dr. Reuber's diagnoses would make the liver
cancers significant because of their rarity. This changes the
equivocal finding of the board to at least some evidence or clear
evidence of carcinogenicity. In addition, the oral changes in the
report were down-graded from dysplasia and metaplasia to degeneration.
Dr. Reuber said that this change should also be reviewed. The report
also down-graded adrenal pheochromocytomas and tumors to hyperplasia.
This needs to be reviewed by an independent board. The other liver
carcinomas were down-graded to foci by artificially defining a need
for 75% compression in the tumor before it was no longer a foci.
Using this changed definition carcinomas were down-graded to adenomas
and adenomas downgraded to eosinophilic foci. In almost
all instances, the Battelle board certified pathologists' findings
were down-graded. It is my
suggestion that a board independent of NIEHS should be assembled
by ODW consisting of human pathologists (for their experience in
diagnosing osteosarcoma), the Battelle pathologist (to defend his
original diagnoses), Dr. Melvin Reuber, Dr. Thomas Squires and two
other well known independent board-certified animal pathologists.
The charge to this board is to meet as a body, review the slides,
agree on a pathologic diagnoses and prepare a report to be submitted
to ODW for incorporation in our docket for the fluoride regulation.
The report talks about the efficacy of fluoride and tooth decay.
Since the studies were performed to determine the carcinogenicity
of fluoride this should not have been addressed. There appear to
be at least four different publications from the U.S., Canada, and
New Zealand that have reported similar or lower tooth decay rates
in nonfluoridated areas as compared to fluoridated areas (4,5,6,7).
Therefore, the entire question of the efficacy of fluoridation based
on extensive and multiple studies has been called into question.
Our job is to set safe levels for fluoride in drinking water based
on the scientific evidence.
The problem with this meeting was the inability of independent reviewers
to get to see the slides prior to the meeting. We must perform our
own scientific review of the slides and write our conclusions for
use in the development of the revised fluoride regulation.
(1) Roa, G.N., and Knappa, J.J. 1987. Contaminant and nutrient
concentrations of natural ingredient rat and mouse diet used in
chemical toxicology studies. Fundam. Appl. Toxicol.
9, 329-338.
(2) Zipkin, L., McClure, F.J., Leone, H.C., and Lee, W.A. 1958.
Fluoride deposition in human bones after prolonged ingestion of
fluoride in drinking water. Public Health Rep. 73,
732-740.
(3) Graham, J.R., Burk, O., and Morin, P. 1987. A current restatement
and continuing reappraisal concerning demographic variables in American
time-trend studies an water
fluoridation and human cancer. Proc Pennsylvania Academy of Sci.
61:138-146.
(4) Colquhoun, J. 1987. Comm. Health Studies. 11:85.
(5) Gray, a. 1987. J. Canadian Dental Assoc. 53:763.
(6) Hildebolt, C.F. et al. 1989. Amer J, Physiol. Anthropol. 78:79-92.
(7) Diesendorf, M. 1986. Nature. 321:125.
NOTE: Due to his criticisms of the tumor downgradings,
Dr. Marcus was fired by the EPA. The US Secretary
of Labor, Robert Reich, later ruled that EPA fired Marcus out of
"retaliation" for Marcus' stance on fluoride, and ordered
EPA to reinstate Marcus with full back pay and compensation. To
learn more about EPA's firing of Marcus, see:
To learn more about the NTP Cancer Study, see:
- Interview with Dr. J. William
Hirzy, Senior Vice President, EPA Headquarters Union -
Interview by Michael Connett, July 2000
- Fluoride bioassay study under scrutiny
- Chemical & Engineering News September 17, 1990
- EPA Scientist Criticizes Downgrading
of Liver & Oral Tumors in Government Fluoride/Cancer Study
- The Lancet September 22, 1990
- Fluoride Linked to Bone Cancer in Fed Study
- Medical Tribune December 28, 1989
- Don't Drink the Water? - Newsweek
February 5, 1990
- Caries preventative already has one rap against
it - Medical Tribune February 22, 1990
- Rat Study Reignites Dispute On Fluoride
- New York Times March 13, 1990
- Weak Link on Fluoride and Cancer Is Backed
- New York Times April 27, 1990
- ACSH Considers Taking Legal Action Against
Attempts to Reclassify Fluoride - Food Chemical News April
30, 1990
- The Risks of Fluoride: The Long Awaited Verdict
Newsweek May 7, 1990
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