Key words: fluoride, bone strength, bone density, radiographic testing, mechanical testing, tech support, research
Various kinds of toxicity have been attributed to ingestion of fluoride, including dental fluorosis; bone fracture; reproductive, renal, gastrointestinal, and immunological toxicities; genotoxicity; and carcinogenicity. In 1990, a study by the PHS National Toxicology Program (NTP) found equivocal evidence of carcinogenicity associated with fluoride ingestion, based on a small number of osteosarcomas in male rats. In response to this finding, a subcommittee of the PHS Committee to Coordinate Environmental Health and Related Programs (CCEHRP) conducted a thorough review of the benefits and risks of water fluoridation and other sources of fluoride. The committee issued a report in 1991 recommending further study related to various regulatory requirements for fluoride. Regarding fluorides effects on bone, CCEHRP recommended research to (1) determine the risk factors associated with the development of fluoride-associated osteosarcoma, and (2) further elucidate the mechanisms of fluoride action on bone at the molecular and physical chemical levels.
A collaborative study between CFSAN and CDRH was undertaken in response to the CCEHRP recommendations. The objective was to determine the levels of fluoride in the plasma, urine, and bone of rats at various stages of development and to characterize the bone strength for those rats. For each category of rat (male/female and pregnant/not pregnant at various stages--neonatal, weanling, and adult), five fluoride levels were studied (0 to 250 ppm in drinking water). CFSAN determined the fluoride content of one femur from each rat and CDRH conducted radiographic and mechanical testing on the contralateral femora to assess the effects of treatment on bone strength. For the radiographic imaging part of the study, computerized tomography testing was performed to measure bone density in the mid-diaphyseal and distal sections of the bone. This enabled study of the effects of treatment on both cortical and trabecular bone. Plain-film radiographs of each bone were also made for a collaborative study with the University of Chicago using fractal analysis to estimate bone strength. Results from these imaging studies will be compared with results from mechanical (bending) tests on the bones to determine (1) the developmental effects of fluoride on bone strength, and (2) the correlation between bone density, fractal dimension and bone strength. Testing has been completed by DMMS and DECS, and the data are being analyzed.
Impact: The Environmental Protection Agency (EPA) regulates fluoride levels in drinking water and FDA regulates fluoride in toothpaste, other dental products (e.g., composite fillings and dental cements), bottled water, water used in food processing, infant formula, and dietary supplements. This study will provide FDA (and possibly EPA) with additional data to address regulatory concerns identified in the CCEHRP report on the benefits and risks of fluoride. The part of the study examining correlation between mechanical and radiographic test data may be of use to CDRH, CDER, CBER, and perhaps others with respect to evaluating imaging devices used to predict fracture risk, bone substitute materials, drugs used to treat or prevent osteoporosis, and methods for storing bone and bone marrow for transplant.