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Ion ~ ~1P Response

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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.'

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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.

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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 ! - .,N,,, ~ ~ - c~.~ W Lent C. Johnson, M.D. Orthopedic Research