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:
