Abstract
The increasing body weights and the associated increased tumor incidences observed in recent long-term rodent bioassays may adversely affect study sensitivity for detecting rodent carcinogenicity. For example, increasing body weights may result in reduced survival and fewer animals at risk for tumor development. Moreover, the increased control tumor incidences observed in the more recent studies make it more difficult to establish firm baseline values and to use historical control data in the overall evaluation of experimental results. Finally, if dosed animals are significantly lighter than controls within a given study, then it may be more difficult to detect carcinogenic effects for those tumor sites sensitive to body weight changes. One approach to deal with this problem is food restriction, and the recently completed NTP Dietary Restriction Study confirmed that reducing food intake can reduce background tumor rates in control animals. There was also a slight increase in survival (approximately 2 wk on average) in the food restricted animals. However, the experimental protocol that restricted food consumption in both dosed and control groups appeared to have reduced sensitivity for detecting carcinogenic effects relative to the standard NTP protocol. One important, but often overlooked, issue when considering dietary restriction is that tumor incidence profiles may differ for animals of equivalent body weight, depending upon how the reduced body weights were achieved. An evaluation of data from NTP long-term rodent studies and from the NTP Dietary Restriction Study indicates that food restricted animals show a significant reduction in a number of site-specific tumors relative to equivalently sized ad libitum-fed animals. These results suggest that a dietary restriction strategy that focuses on achieving similar body weights in dosed and control groups may produce false positive outcomes if substantially more food restriction is required for control groups than for dosed animals (e.g., if control animals must receive a moderate (15—20%) degree of food restriction to achieve body weights equivalent to those observed in ad libitum-fed dosed animals). Results from the NTP Dietary Restriction Study also demonstrate that a moderate (15—20%) food restriction protocol applied equally to dosed and control animals may produce false negative outcomes if the resulting body weights are substantially different in dosed and control groups. Alternative strategies for reducing body weights are briefly discussed, but at present it is unclear which strategy or combination of strategies will ultimately prove to be most effective for dealing with the problem of increasing body weights.