Although the subsequent review by AFIP considered these mouse osteomas as more closely resembling hyperplasia than neoplasia, given that osteoma is widely recognized as neoplastic, the evidence of osteoma remains important in the overall weight-of-evidence consideration. The increased incidence and severity of osteosclerosis in high-dose female rats in the NTP study demonstrated the mitogenic effect of fluoride in stimulating osteoblasts and osteoid production (NTP 1990) (see also Chapter 5).

The genotoxicity data, particularly from in vivo human studies, are also conflicting; whereas three were positive on the basis of the ingestion route (Sheth et al. 1994; Wu and Wu 1995; Joseph and Gadhia 2000), all three of these reports had serious deficits in design and/or reporting, including the characterization of how the study populations were selected and whether the exposed and unexposed study subjects were comparable. Two studies (Meng et al. 1995; Meng and Zhang 1997) were positive for the inhalation route among workers in a phosphate fertilizer factory, although other contaminants cannot be ruled out as the causal factors. Contrasting negative observations by other investigators (Li et al. 1995; Jackson et al. 1997; Van Asten et al. 1998) must also be considered.

• The results of the Douglass et al. multicenter osteosarcoma study (expected in the summer of 2006) could add important data to the current body of literature on fluoride risks for osteosarcoma because the study includes bone fluoride concentrations for cases and controls. When this study is published, it should be considered in context with the existing body of evidence to help determine what follow-up studies are needed.

• Further research on a possible effect of fluoride on bladder cancer risk should be conducted. Since bladder cancer is relatively common (compared with osteosarcoma), both cohort and case-control designs would be feasible to address this question. For example, valuable data might be yielded by analyses of cancer outcomes among the cohorts followed for other health outcomes, such as fractures (see Chapter 5).

• The positive in vivo genotoxicity studies described in the chapter were conducted in India and China, where fluoride concentrations in drinking water are often higher than those in the United States. Further, each had a dearth of information on the selection of subjects and was based on small numbers of participants. Therefore, in vivo human genotoxicity studies