function may be a step in the pathway to carcinogenesis. More often, they indicate interference with the normal duplication, function, and control of cell division and genetic activity that also might result in precancer or early neoplastic processes. Genotoxicity also encompasses the ability to cause germ cell and somatic cell mutations that cause malformations, disease, and other adverse health outcomes.

Many cell systems derived from various organisms have been used to the assess genotoxicity of a large array of chemicals. In evaluating the applicability of the results of these tests to human risk from fluoride ingestion, some of the key parameters are the concentrations used in the assays compared with physiologic concentrations, the form and vehicle for fluoride exposure in the assay, and existing data on overall applicability of the various assays to risk in humans. Tennant (1987) and Tennant et al. (1987) concluded that the Salmonella reverse mutation assay was the best short-term genotoxicity assay available for predicting carcinogenicity in mammals. However, Parodi et al. (1991) reviewed the results of various genotoxicity tests in comparison with animal carcinogenicity studies, and found that in vitro cytogenetic tests, particularly sister-chromatid exchange tests (SCEs), were more predictive of carcinogenicity than the Salmonella reverse mutation assay. Tice et al. (1996) subsequently reviewed relative sensitivities of rodents and humans to genotoxic agents and concluded that humans are more than an order of magnitude more sensitive than rodents to most of the genotoxic agents they examined using the genetic activity profile database.

The available new genotoxicity studies of fluoride are detailed in Table 10-1. The most extensive and important additions to the genotoxicity literature on fluoride since 1993 are in vivo assays in human populations and, to a lesser extent, in vitro assays using human cell lines and in vivo experiments with rodents. These studies are discussed below.

Gene Mutation

Mutagenicity indicates direct action of a substance on DNA. Alterations in DNA suggest that the chemical has the potential to cause genetic effects as well as carcinogenic potential. In 1993, the existing literature did not indicate that fluoride posed a mutation hazard. The literature included assays with Salmonella (virtually all negative results), various mammalian cells lines (virtually all negative), and cultured human lymphocytes. Positive results in the human lymphocytes were seen at fluoride concentrations above 65 micrograms per milliliter (µg/mL) (parts per million [ppm]) and generally at more than 200 µg/mL, (much greater concentrations than those to which human cells in vivo typically would be exposed). No pertinent studies have been found since those reviewed in the 1993 NRC report. The committee interprets the weight of evidence from in vivo rodent studies to



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