SOURCES OF VARIABILITY IN TUMOR INCIDENCE IN LONG TERM RODENT STUDIES

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Summary of Work: An evaluation of data 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. We also found that equal food restriction to dosed and control animals may produce false negative outcomes if the resulting body weights are substantially different in dosed and control groups. An evaluation of correlations between the occurrence of site-specific tumors revealed little meaningful associations except for a strong negative correlation between the incidences of pituitary gland and testis tumors in male F344 rats. Mechanistic arguments were given to explain how differences in caging protocols may have been responsible for this observed negative correlation in tumor response. We evaluated the frequency of chemically- related decreases in tumor incidence in NTP studies. Many of these decreases are associated with the reduced body weights frequently observed in the dosed groups. The chemically-related decreased incidences of leukemia in rats appear to be related to spleen damage, i.e., chemically-related splenic toxicity is evident for most chemicals showing decreased incidences of leukemia. We concluded that most chemically-related tumor decreases observed in NTP studies are due to either random variability, associations with body weight, or (in the case of leukemia) splenic toxicity.