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OCR for page 177
Ion ~
~1P Response
OCR for page 178
OCR for page 179
Appendix 179
_.
REPLY TO
AnENTION OF
Kulbir S. Bakshi, Ph.D.
National Research Council
2101 Constitution Ave
Washington, D.C. 20418
Dear Dr. Bakshi:
DEPARTMENT OF DEFENSE
ARMED FORCES INSTITUTE OF PATHOLOGY
WASHINGTON DC 20306-6000
October 14, 1992
On 29 September, 1992, in response to your letter dated 24
July, 1992, the Proctor and Gamble mouse fluoride study was
reviewed in part at Hazleton Laboratories, Madison, Wisconsin.
Present were Drs. Michael Slayter (AFIP), Lent Johnson (AFIP),
Steven Weisbrode (The Ohio State University), Byron Boysen
(Hazleton Laboratories), and James Maurer (Procter and C,~mbl eN
Due to time constraints,
representative sample of
our review was limited to a
_ _ ,_ _ bone sections on glass slides from each
treatment group. The underlying purpose of this review was to
accurately answer the eight specific questions you have posed in
the above cited letter. Our response follows:
1. We gather from your letter that the primary lesions of
concern are those termed hyperostosis and osteoma. This
terminology is correctly used in the study and falls within the
limits of time-honored academic definition. As stated in the
study, hyperostosis is, 'a term used to describe excessive
formation of non-neoplastic bone. The lesion may be focal,
multifocal, or diffuse. Morphologically, hyperostoses are
characterized by the presence of excessive amounts of woven or
lamellar bone or both. Borders between normal bone and areas of
hyperostoses cannot usually be distinguished morphologically. In
this study, the areas of hyperostoses tended to be bilaterally
symmetrical and characterized by irregular deposition of mature
lamellar bone primarily in, but not limited to, subperiosteal
regions, resulting in excessively thick cortical regions.
Although these lesions were also found in other bones, the
incidence and severity were much greater for bones of the head.'
~. . . . .
Likewise, osteoma is stated as, 'a term used to describe a benign
neoplasm arising from osteoblasts. Morphologically, osteomas are
usually composed of abundant osteoids/matrix arranged in a
spicular pattern and forming spherical masses that have distinct
borders that are clearly distinguished from, but attached to,
normal bone. The neoplastic bone may be woven or lamellar.
These neoplasms are generally distinguished from hyperplastic
lesions because osteomas are circumscribed and clinically may
continue to grow by expansion after being detected. Osteomas are
slow growing expansive lesions and do not metastasize.'
OCR for page 180
180 Health Effects of Ingested Fluoride
Kulbir S. Bakshi, Ph.D.
Page two
Two additional terms which were used less frequently in the
study, and which may surface in your subsequent discussions are
osteosclerosis and enostosis. These terms indicated diffuse and
localized ossification of the medullary cavity, respectively.
The definition of other more incidental lesions are also
addressed in the Hazleton report (HLA 81190).
2. Human osteomas are often considered neoplasms, but some
authors doubt that they represent true neoplasms. They are
regarded by some as hamartomas, a General term which can be
applied broadly to a mass of disorganized, mature, specialized
cells or tissue which is indigenous to a particular site, but
present in the wrong proportions. An accurate definition of
"neoplasm" is surprisingly difficult to establish. The British
oncologist Sir Rupert Willis provided the best when he wrote, ''A
neoplasm is an abnormal mass of tissue, the growth of which
exceeds and is uncoordinated with that of the normal tissues and
persists in the same excessive manner after cessation of the
stimuli which evoked the change." We agree that the osteomas
reported in this study are virally induced growths but not true
neoplasms; if the evoking virus was removed, the lesion would
persist only as an anomaly in both the controls and the fluoride
treated animals. Extrapolation to humans is impossible as no
comparable situation is known to occur.
. .
3 The osteomas in this study did not appear to result from
the progression of the hyperostoses, nor is the reverse true.
4. Inasmuch as no malignant bone tumors were seen among the
many osteomas in the study, we conclude that these osteomas do
not progress to a malignant form.
5. True neoplasms do not regress. Removal of the virus is
a hypothetical question and difficult to address. Fluoride-
induced changes would eventually regress after removal of the
fluoride; however, it is doubtful that one could appreciate any
substantial regression of the osteoma in the short life span of a
mouse.
6. Primary bone neoplasms are rarely multicentric in
animals. Two notable exceptions are feline osteochondromatosis
(which may not be a true neoplasm) and viral induced tumors of
the mouse.
7. Within the experience of the panel, there is no human
counterpart to a fluoride-viral bone perturbation seen in the
mice of this study.
OCR for page 181
Apperldix 181
Kulbir S. Bakshi, Ph.D.
Page three
8. Evidence to support a retrovirus infection consists of
finding numerous C-type retrovirus particles associated with
osteoblasts in all osteomas ultrastrueturally examined,
regardless of whether they occurred in control mice or mice
treated with NaF. Retroviruses are known to cause osteomas in
mice. Additionally, the locations, multiplicity and morphologic
features of the osteomas in all groups were consistent with those
associated with virus-induced bone tumors. Attempts to fulfill
Koeh's postulate by infecting mice with retrovirus from the study
to demonstrate it would induce osteomas were unsuccessful.
However, the presence of numerous retrovirus particles in all
osteomas examined is highly suggestive of its involvement in the
induction of the osteomas.
Thank you for the opportunity to be of service.
John M. Pleteher, DVM, MPH
Colonel, VC, USA
Chairman, Department of Veterinary Pathology
?~iC~ l/~
Michael V. Slayte~, DVM, MPVM
Chief, Research Branch
Department of Veterinary Pathology
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.,N,,, ~ ~ - c~.~ W
Lent C. Johnson, M.D.
Orthopedic Research
Representative terms from entire chapter:
hazleton laboratories
