Review of mononuclear cell leukemia in F-344 rat bioassays and its significance to human cancer risk: A case study using alkyl phthalates

Elevated incidences of mononuclear cell leukemia (MNCL) have been observed in a number of chronic bioassays in the F-344 rat. As this tumor type is unique to the rat and is only common in the F-344 strain, its significance for human cancer risk is unclear. For this reason, a survey of the published literature was undertaken to assess the occurrence and etiology of MNCL in F-344 rats and to evaluate its potential significance to humans using alkyl phthalate data as an example. It was found that MNCL occurs in untreated, aged F-344 rats at a high and variable rate, it is uncommon in most other rat strains, and its background incidence has increased significantly over time. This complicates retrospective data interpretation. MNCL has not been found in other mammalian species and no histologically comparable tumor is found in humans. In general, a statistically significant increase in frequency of a common tumor in the F-344 rat is an insufficient basis for determining that a chemical presents a carcinogenic hazard to humans, particularly when that tumor is not observed in other species. As one example, the alkyl phthalates constitute one group of substances which has been associated with increased MNCL frequency in the F-344 rat after high dietary doses. In evaluating the significance of this increase in MNCL, an extensive toxicological database for phthalates indicates that toxicological effects occur only at relatively high doses, and tumor development (including MNCL) occurs only after an apparent threshold is exceeded. Phthalates are not genotoxic as a class, further supporting the hypothesis of the existence of a threshold. When these considerations are collectively evaluated, it can be concluded that a finding of increased MNCL in F-344 rats exposed for a lifetime to a nongenotoxic chemical is not toxicologically relevant to humans, even when MNCL is observed at an increased incidence that is statistically significant. Thus, the increased incidence of MNCL observed in F-344 rats exposed to some alkyl phthalates is likely a strain-specific effect of little or no relevance for humans, and characterization of these chemicals as carcinogens based on increased MNCL in F-344 rats is not scientifically supported. (C) 1999 Academic Press.